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Hu X, Li L, Nkwocha J, Kmieciak M, Shang S, Cowart LA, Yue Y, Horimoto K, Hawkridge A, Rijal A, Mauro AG, Salloum FN, Hazlehurst L, Sdrimas K, Moore Z, Zhou L, Ginder GD, Grant S. Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia. Signal Transduct Target Ther 2025; 10:50. [PMID: 39924517 PMCID: PMC11808118 DOI: 10.1038/s41392-025-02125-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 11/14/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. However, their effectiveness in acute myeloid leukemia (AML) is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system. Here, we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g., bosutinib (SKI-606) might circumvent this phenomenon. MCL-1 antagonist/SKI-606 co-administration synergistically induced apoptosis in diverse AML cell lines. Consistently, Src or MCL-1 knockdown with shRNA markedly sensitized cells to MCL-1 inhibitors or SKI-606 respectively, while ectopic MCL-1 expression significantly diminished apoptosis. Mechanistically, MCL-1 antagonist exposure induced MCL-1 up-regulation, an event blocked by Src inhibitors or Src shRNA knock-down. MCL-1 down-regulation was associated with diminished transcription and increased K48-linked degradative ubiquitination. Enhanced cell death depended functionally upon down-regulation of phosphorylated STAT3 (Tyr705/Ser727) and cytoprotective downstream targets c-Myc and BCL-xL, as well as BAX/BAK activation, and NOXA induction. Importantly, the Src/MCL-1 inhibitor regimen robustly killed primary AML cells, including primitive progenitors, but spared normal hematopoietic CD34+ cells and human cardiomyocytes. Notably, the regimen significantly improved survival in an MV4-11 cell xenograft model, while reducing tumor burden in two patient-derived xenograft (PDX) AML models and increased survival in a third. These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination, disrupting STAT-3-mediated transcription, and inducing NOXA-mediated MCL-1 degradation. They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies.
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Affiliation(s)
- Xiaoyan Hu
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Lin Li
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Jewel Nkwocha
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Maciej Kmieciak
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Shengzhe Shang
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - L Ashley Cowart
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA
| | - Yang Yue
- Office of the Vice President for Research Infrastructure, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Adam Hawkridge
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA
| | - Arjun Rijal
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Adolfo G Mauro
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Fadi N Salloum
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Lori Hazlehurst
- Department of Pharmaceutical Science, WVU Cancer Institute, Morgantown, WV, USA
| | | | - Zackary Moore
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Liang Zhou
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
- Department of Translational Medicine, Asklepios BioPharmaceutical, Inc., Durham, NC, USA
| | - Gordon D Ginder
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven Grant
- Division of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
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Kotzer HN, Capera J, Jainarayanan A, Mayya V, Zanin-Zhorov A, Valvo S, Macdonald J, Taylor PC, Dustin ML. STAT3 phosphorylation in the rheumatoid arthritis immunological synapse. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.20.633875. [PMID: 39896614 PMCID: PMC11785017 DOI: 10.1101/2025.01.20.633875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naïve CD4+ T cells. Our data demonstrates that Lck mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic Lck/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
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Affiliation(s)
- Hila Novak Kotzer
- Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY 10016 USA
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
| | - Jesusa Capera
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
| | - Ashwin Jainarayanan
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
| | - Viveka Mayya
- Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY 10016 USA
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
| | - Alexandra Zanin-Zhorov
- Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY 10016 USA
| | - Salvatore Valvo
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
| | - Joanne Macdonald
- Botnar Institute for Musculoskeletal Sciences, NDORMS, University of Oxford, Oxford, OX3 7LD UK
| | - Peter C. Taylor
- Botnar Institute for Musculoskeletal Sciences, NDORMS, University of Oxford, Oxford, OX3 7LD UK
| | - Michael L Dustin
- Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY 10016 USA
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY UK
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You N, Liu G, Yu M, Chen W, Fei X, Sun T, Han M, Qin Z, Wei Z, Wang D. Reconceptualizing Endothelial-to-mesenchymal transition in atherosclerosis: Signaling pathways and prospective targeting strategies. J Adv Res 2025:S2090-1232(24)00627-1. [PMID: 39756576 DOI: 10.1016/j.jare.2024.12.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 12/27/2024] [Accepted: 12/28/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND The modification of endothelial cells (ECs) biological function under pathogenic conditions leads to the expression of mesenchymal stromal cells (MSCs) markers, defined as endothelial-to-mesenchymal transition (EndMT). Invisible in onset and slow in progression, atherosclerosis (AS) is a potential contributor to various atherosclerotic cardiovascular diseases (ASCVD). By triggering AS, EndMT, the "initiator" of AS, induces the progression of ASCVD such as coronary atherosclerotic heart disease (CHD) and ischemic cerebrovascular disease (ICD), with serious clinical complications such as myocardial infarction (MI) and stroke. In-depth research of the pathomechanisms of EndMT and identification of potential targeted therapeutic strategies hold considerable research value for the prevention and treatment of ASCVD-associated with delayed EndMT. Although previous studies have progressively unraveled the complexity of EndMT and its pathogenicity triggered by alterations in vascular microenvironmental factors, systematic descriptions of the most recent pathogenic roles of EndMT in the progression of AS, targeted therapeutic strategies, and their future research directions are scarce. AIM OF REVIEW We aim to provide new researchers with comprehensive knowledge of EndMT in AS. We exhaustively review the latest research advancements in the field and provide a theoretical basis for investigating EndMT, a biological process with sophisticated mechanisms. KEY SCIENTIFIC CONCEPTS OF REVIEW This review summarized that altered hemodynamics with microenvironmental crosstalk consisting of inflammatory responses or glycolysis, oxidative stress, lactate or acetyl-CoA (Ac-CoA), fatty acid oxidation (FAO), intracellular iron overload, and transcription factors, including ELK1 and STAT3, modulate the EndMT and affect AS progression. In addition, we provide new paradigms for the development of promising therapeutic agents against these disease-causing processes and indicate promising directions and challenges that need to be addressed to elucidate the EndMT process.
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Affiliation(s)
- Nanlin You
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Guohao Liu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Mengchen Yu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Wenbo Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiaoyao Fei
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Tao Sun
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Mengtao Han
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zhen Qin
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zhaosheng Wei
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Donghai Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, Shandong 253032, China.
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Yue P, Chen Y, Ogese MO, Sun S, Zhang X, Esan T, Buolamwini JK, Turkson J. Small Molecule Induces Time-Dependent Inhibition of Stat3 Dimerization and DNA-Binding Activity and Regresses Human Breast Tumor Xenografts. Chembiochem 2024; 25:e202400351. [PMID: 39168826 DOI: 10.1002/cbic.202400351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/26/2024] [Accepted: 08/21/2024] [Indexed: 08/23/2024]
Abstract
Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 μM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 μM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, and Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1, pErk1/2MAPK, pShc, pJAK2, or pSrc induction, or on cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.
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Affiliation(s)
- Peibin Yue
- Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Yue Chen
- Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
- Current adress: Department of Basic Medicine, Suzhou Vocational Health College, Suzhou, 215009, China
| | - Monday O Ogese
- Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
| | - Shan Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis, TN, 38163, USA
| | - Xiaolei Zhang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical, Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Taiwo Esan
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064-3095, USA
| | - John K Buolamwini
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis, TN, 38163, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064-3095, USA
| | - James Turkson
- Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA
- Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA
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Li H, Fang G, Tian W, Liao Y, Xiang J, Hu Y, Luo L. Asiatic acid induces lung cancer toxicity by triggering SRC-mediated ferroptosis. Toxicol Appl Pharmacol 2024; 492:117097. [PMID: 39251043 DOI: 10.1016/j.taap.2024.117097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 08/12/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024]
Abstract
Ferroptosis is a recently discovered form of regulated cell death that shows promise as a novel approach for inducing tumor cell death in cancer treatment, with significant research potential. Asiatic acid (AA), a key component of the traditional Chinese medicine Centella asiatica, has been identified as having potential therapeutic benefits for various diseases, particularly cancer. Non-small cell lung cancer (NSCLC) is a challenging and prevalent form of cancer to treat. In our study, we utilized network pharmacology, molecular docking, and experimental methods to investigate the potential of AA in treating NSCLC and to elucidate its role in inhibiting cancer through the ferroptosis pathway. Through network pharmacology analysis, we identified that AA targets the core NSCLC protein SRC through the ferroptosis pathway. Our experiments demonstrated that treatment with AA led to increased iron accumulation, mitochondrial membrane potential, and expression of ferroptosis markers glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and acyl-CoA synthetase long chain family member 4 (ACSL4) in NSCLC cells, confirming the induction of ferroptosis. In conclusion, AA has the potential to target SRC and induce NSCLC cell death through the ferroptosis pathway, offering a promising approach for cancer treatment.
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Affiliation(s)
- Huizhen Li
- The First Clinical College, Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Guixuan Fang
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Wen Tian
- The First Clinical College, Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Yinglin Liao
- The First Clinical College, Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Jing Xiang
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China
| | - Yingying Hu
- Department of Pathophysiology, Guangdong Medical University, Zhanjiang 524002, Guangdong, China
| | - Lianxiang Luo
- The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong 524023, China.
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de Barros FD, Guimarães GC, Martins MR, Marinho FDS, Soares FA, Torres LC. Expression of CD44 highCD24 Low cells, SOX2, and STAT3 transcription factors on peripheral blood and tumor tissue of penile squamous cell carcinoma. J Surg Oncol 2024. [PMID: 39155672 DOI: 10.1002/jso.27749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/13/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND Penile cancer is high in some underdeveloped countries. Signal transducer and activator of transcription 3 (STAT3) and CD44, CD24, and SOX2+ are known to be markers of diagnosis and prognosis in other cancers, but without studies in penile cancer. METHODS A cross-sectional study was conducted at the Hospital de Cancer de Pernambuco from March 2015 to December 2017. We performed SOX2, STAT3, CD24, and CD44 analyses in blood and tumor tissue by flow cytometry. RESULTS High levels of CD44highCD24low, CD44highCD24lowpSTAT3+ and CD44hig hCD24low in the blood of patients compared to the controls (p < 0.05). Low of SOX2+ T cells in blood of patients compared to controls. High CD44highCD24low levels in patients with perineural invasion (PNI), tumor size > 3 cm, and pT2 stage (p < 0.05). High T cell levels in the blood and tumor tissue of patients with tumor ≤3 cm (p < 0.05). Increased SOX2+ T cells in blood of patients with PNI (-) and pT1 stage (p < 0.05). CD44highCD24lowpSTAT3+ (r = 0.669; p = 0.024) and SOX2+T cells (r = 0.404, p = 0.029) correlation were observed between blood and tumor tissue in penile cancer patients. CONCLUSION CD44, CD24, and SOX2 molecules were markers of advanced disease associated with the worst prognosis in CaPe. However, pSTAT3 and T cells were associated with a more favorable prognosis in this study.
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Affiliation(s)
- Felipe Dubourcq de Barros
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Hospital de Câncer de Pernambuco, Recife, Brazil
- Postgraduate Program in Translational Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Mário Rino Martins
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Hospital de Câncer de Pernambuco, Recife, Brazil
- Postgraduate Program in Translational Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Felipe da Silva Marinho
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Hospital de Câncer de Pernambuco, Recife, Brazil
- AC Camargo Cancer Center, São Paulo, Brazil
| | | | - Leuridan Cavalcante Torres
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Hospital de Câncer de Pernambuco, Recife, Brazil
- Postgraduate Program in Translational Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
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Zhu C, Fan F, Li CY, Xiong Y, Liu X. Caspase-3 promotes oncogene-induced malignant transformation via EndoG-dependent Src-STAT3 phosphorylation. Cell Death Dis 2024; 15:486. [PMID: 38977663 PMCID: PMC11231138 DOI: 10.1038/s41419-024-06884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.
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Affiliation(s)
- Chenchen Zhu
- Department of Biochemistry, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Fushun Fan
- BeBetter Med Inc., Guangzhou, Guangdong, China
| | - Chuan-Yuan Li
- Department of Dermatology, Duke University Medical Center, Durham, NC, USA
| | - Yan Xiong
- Guangzhou Consen Pharmaceutical Technology Co. Ltd, Guangzhou, Guangdong, China.
| | - Xinjian Liu
- Department of Biochemistry, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.
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Marugán C, Sanz‐Gómez N, Ortigosa B, Monfort‐Vengut A, Bertinetti C, Teijo A, González M, Alonso de la Vega A, Lallena MJ, Moreno‐Bueno G, de Cárcer G. TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling. Mol Oncol 2024; 18:1531-1551. [PMID: 38357786 PMCID: PMC11161735 DOI: 10.1002/1878-0261.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/03/2024] [Accepted: 01/26/2024] [Indexed: 02/16/2024] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.
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Grants
- 2018-20I114 Spanish National Research Council (CSIC)
- 2021-AEP035 Spanish National Research Council (CSIC)
- 2022-20I018 Spanish National Research Council (CSIC)
- FJC2020-044620-I Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2019-104644RB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2021-125705OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2022-136854OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- RTI2018-095496-B-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- CB16/12/00295 Instituto de Salud Carlos III - CIBERONC
- LABAE16017DECA Spanish Association Against Cancer (AECC) Scientific Foundation
- POSTD234371SANZ Spanish Association Against Cancer (AECC) Scientific Foundation
- PROYE19036MOR Spanish Association Against Cancer (AECC) Scientific Foundation
- Spanish National Research Council (CSIC)
- Spanish Association Against Cancer (AECC) Scientific Foundation
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Affiliation(s)
- Carlos Marugán
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Natalia Sanz‐Gómez
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Beatriz Ortigosa
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Monfort‐Vengut
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Cristina Bertinetti
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Teijo
- Pathology DepartmentMD Anderson Cancer CenterMadridSpain
| | - Marta González
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Alicia Alonso de la Vega
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - María José Lallena
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Gema Moreno‐Bueno
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- MD Anderson International FoundationMadridSpain
- Biomedical Cancer Research Network (CIBERONC)MadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
| | - Guillermo de Cárcer
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
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9
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Jiang H, Yang J, Li T, Wang X, Fan Z, Ye Q, Du Y. JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target. Front Pharmacol 2024; 15:1336102. [PMID: 38495094 PMCID: PMC10940489 DOI: 10.3389/fphar.2024.1336102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/18/2024] [Indexed: 03/19/2024] Open
Abstract
Cardiac fibrosis is a serious health problem because it is a common pathological change in almost all forms of cardiovascular diseases. Cardiac fibrosis is characterized by the transdifferentiation of cardiac fibroblasts (CFs) into cardiac myofibroblasts and the excessive deposition of extracellular matrix (ECM) components produced by activated myofibroblasts, which leads to fibrotic scar formation and subsequent cardiac dysfunction. However, there are currently few effective therapeutic strategies protecting against fibrogenesis. This lack is largely because the molecular mechanisms of cardiac fibrosis remain unclear despite extensive research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade is an extensively present intracellular signal transduction pathway and can regulate a wide range of biological processes, including cell proliferation, migration, differentiation, apoptosis, and immune response. Various upstream mediators such as cytokines, growth factors and hormones can initiate signal transmission via this pathway and play corresponding regulatory roles. STAT3 is a crucial player of the JAK/STAT pathway and its activation is related to inflammation, malignant tumors and autoimmune illnesses. Recently, the JAK/STAT3 signaling has been in the spotlight for its role in the occurrence and development of cardiac fibrosis and its activation can promote the proliferation and activation of CFs and the production of ECM proteins, thus leading to cardiac fibrosis. In this manuscript, we discuss the structure, transactivation and regulation of the JAK/STAT3 signaling pathway and review recent progress on the role of this pathway in cardiac fibrosis. Moreover, we summarize the current challenges and opportunities of targeting the JAK/STAT3 signaling for the treatment of fibrosis. In summary, the information presented in this article is critical for comprehending the role of the JAK/STAT3 pathway in cardiac fibrosis, and will also contribute to future research aimed at the development of effective anti-fibrotic therapeutic strategies targeting the JAK/STAT3 signaling.
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Affiliation(s)
- Heng Jiang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Junjie Yang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Tao Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xinyu Wang
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Zhongcai Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qiang Ye
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yanfei Du
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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10
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Adesoye T, Tripathy D, Hunt KK, Keyomarsi K. Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics. Cancers (Basel) 2024; 16:492. [PMID: 38339245 PMCID: PMC10854592 DOI: 10.3390/cancers16030492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 02/12/2024] Open
Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.
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Affiliation(s)
- Taiwo Adesoye
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Debasish Tripathy
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Kelly K. Hunt
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Khandan Keyomarsi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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11
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Rahbar Farzam O, Najafi S, Amini M, Rahimi Z, Dabbaghipour R, Zohdi O, Asemani Shahgoli G, Baradaran B, Akbari B. Interplay of miRNAs and lncRNAs in STAT3 signaling pathway in colorectal cancer progression. Cancer Cell Int 2024; 24:16. [PMID: 38185635 PMCID: PMC10771635 DOI: 10.1186/s12935-023-03202-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024] Open
Abstract
In recent decades, colorectal cancer (CRC) has turned into one of the most widespread malignancies, and the incidence of this malignancy is expected to increase. Despite considerable improvements in therapeutic approaches, the prognosis, and the management of CRC face many problems. Likely, the main limitation in the successful treatment of CRC is the lack of appropriate clinical therapeutic targets. As an effective target, the signal transducer and activator of transcription 3 (STAT3) are regulated by a wide range of genes and involved in cellular processes, including cell growth, migration, invasion, immunosuppression, and angiogenesis. Aberrant regulation of STAT3 signaling leads to cellular dysfunction, diseases, and malignancies, including CRC. Consequently, targeting this signaling pathway is considered one of the therapeutic strategies used in CRC treatment. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA molecules with partial or no protein-coding activity that participate in gene regulation at epigenetic, transcriptional, and post-transcriptional levels and regulate multiple signaling pathways, including STAT3 signaling (especially JAK/STAT). Therefore, these regulatory molecules are suggested to be very promising targets to present new insights into overcoming the limitations of conventional therapeutic strategies. Therefore, the current review study aimed to summarize the therapeutic and diagnostic significance of miRNAs and lncRNAs and their therapeutic and diagnostic significance related to the expression and activity of STAT3 in CRC.
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Affiliation(s)
- Omid Rahbar Farzam
- Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Rahimi
- Department of Clinical Biochemistry, Medical School, Daneshgah Avenue, Kermanshah, Iran
- Medical Biology Research Center, Daneshgah Avenue, Kermanshah, Iran
| | - Reza Dabbaghipour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Zohdi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Akbari
- Department of Medical Biotechnology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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12
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Wang Y, Wang J, Chen L, Chen Z, Wang T, Xiong S, Zhou T, Wu G, He L, Cao J, Liu M, Li H, Gu H. PRRG4 regulates mitochondrial function and promotes migratory behaviors of breast cancer cells through the Src-STAT3-POLG axis. Cancer Cell Int 2023; 23:323. [PMID: 38102641 PMCID: PMC10724894 DOI: 10.1186/s12935-023-03178-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/07/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Breast cancer is the leading cause of cancer death for women worldwide. Most of the breast cancer death are due to disease recurrence and metastasis. Increasingly accumulating evidence indicates that mitochondria play key roles in cancer progression and metastasis. Our recent study revealed that transmembrane protein PRRG4 promotes the metastasis of breast cancer. However, it is not clear whether PRRG4 can affect the migration and invasion of breast cancer cells through regulating mitochondria function. METHODS RNA-seq analyses were performed on breast cancer cells expressing control and PRRG4 shRNAs. Quantitative PCR analysis and measurements of mitochondrial ATP content and oxygen consumption were carried out to explore the roles of PRRG4 in regulating mitochondrial function. Luciferase reporter plasmids containing different lengths of promoter fragments were constructed. Luciferase activities in breast cancer cells transiently transfected with these reporter plasmids were analyzed to examine the effects of PRRG4 overexpression on promoter activity. Transwell assays were performed to determine the effects of PRRG4-regulated pathway on migratory behaviors of breast cancer cells. RESULTS Analysis of the RNA-seq data revealed that PRRG4 knockdown decreased the transcript levels of all the mitochondrial protein-encoding genes. Subsequently, studies with PRRG4 knockdown and overexpression showed that PRRG4 expression increased mitochondrial DNA (mtDNA) content. Mechanistically, PRRG4 via Src activated STAT3 in breast cancer cells. Activated STAT3 in turn promoted the transcription of mtDNA polymerase POLG through a STAT3 DNA binding site present in the POLG promoter region, and increased mtDNA content as well as mitochondrial ATP production and oxygen consumption. In addition, PRRG4-mediated activation of STAT3 also enhanced filopodia formation, migration, and invasion of breast cancer cells. Moreover, PRRG4 elevated migratory behaviors and mitochondrial function of breast cancer cells through POLG. CONCLUSION Our results indicate that PRRG4 via the Src-STAT3-POLG axis enhances mitochondrial function and promotes migratory behaviors of breast cancer cells.
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Affiliation(s)
- Yang Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jieyi Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Lan Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Zhuo Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Tong Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Shuting Xiong
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Tong Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Guang Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Licai He
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Jiawei Cao
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Min Liu
- Department of Orthopedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, Zhejiang, China
| | - Hongzhi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Room 903 and 904, Biomedical Research Building-South, Chashan University Town, Wenzhou, 325035, Zhejiang, China.
| | - Haihua Gu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Room 903 and 904, Biomedical Research Building-South, Chashan University Town, Wenzhou, 325035, Zhejiang, China.
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13
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Mishra A, Kumar A, Naik L, Patel S, Das M, Behura A, Nayak DK, Mishra A, Bhutia SK, Singh R, Dhiman R. Soybean lectin-triggered IL-6 secretion induces autophagy to kill intracellular mycobacteria through P2RX7 dependent activation of the JAK2/STAT3/Mcl-1 pathway. Cytokine 2023; 171:156366. [PMID: 37716189 DOI: 10.1016/j.cyto.2023.156366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 09/18/2023]
Abstract
Cytokine therapy and cytokine-mediated autophagy have been used as prominent host-directed therapy (HDT) approaches to restrain M. tb growth in the host cell. In the present study, we have dissected the anti-tubercular activity of Soybean lectin (SBL) through cytokine-mediated autophagy induction in differentiated THP-1 (dTHP-1) cells. A significant increase in IL-6 expression was observed in both uninfected and mycobacteria infected dTHP-1 cells through the P2RX7 mediated pathway via PI3K/Akt/CREB-dependent signalling after SBL treatment. Inhibition of IL-6 level using IL-6 neutralizing antibody or associated signalling significantly enhanced the mycobacterial load in SBL-treated dTHP-1 cells. Further, autocrine signalling of IL-6 through its receptor-induced Mcl-1 expression activated autophagy via JAK2/STAT3 pathway, and inhibition of this pathway affected autophagy. Finally, blocking the IL-6-regulated autophagy through NSC 33994 (a JAK2 inhibitor) or S63845 (an Mcl-1 inhibitor) led to a notable increase in intracellular mycobacterial growth in SBL-treated cells. Taken together, these results indicate that SBL interacts with P2RX7 to regulate PI3K/Akt/CREB network to release IL-6 in dTHP-1 cells. The released IL-6, in turn, activates the JAK2/STAT3/Mcl-1 pathway upon interaction with IL-6Rα to modulate autophagy that ultimately controls mycobacterial growth in macrophages.
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Affiliation(s)
- Abtar Mishra
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ashish Kumar
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lincoln Naik
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Salina Patel
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Mousumi Das
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Assirbad Behura
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Dev Kiran Nayak
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India
| | - Sujit K Bhutia
- Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ramandeep Singh
- Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, PO Box # 4, Faridabad 121001, Haryana, India
| | - Rohan Dhiman
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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14
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Carter-Su C, Argetsinger LS, Svezhova N. 2022 Cannon lecture: an ode to signal transduction: how the growth hormone pathway revealed insight into height, malignancy, and obesity. Am J Physiol Endocrinol Metab 2023; 325:E425-E437. [PMID: 37672248 PMCID: PMC10874654 DOI: 10.1152/ajpendo.00265.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 09/07/2023]
Abstract
Walter Cannon was a highly regarded American neurologist and physiologist with extremely broad interests. In the tradition of Cannon and his broad interests, we discuss our laboratory's multifaceted work in signal transduction over the past 40+ years. We show how our questioning of how growth hormone (GH) in the blood communicates with cells throughout the body to promote body growth and regulate body metabolism led to insight into not only body height but also important regulators of malignancy and body weight. Highlights include finding that 1) A critical initiating step in GH signal transduction is GH activating the GH receptor-associated tyrosine kinase JAK2; 2) GH activation of JAK2 leads to activation of a number of signaling proteins, including STAT transcription factors; 3) JAK2 is autophosphorylated on multiple tyrosines that regulate the activity of JAK2 and recruit signaling proteins to GH/GH receptor/JAK2 complexes; 4) Constitutively activated STAT proteins are associated with cancer; 5) GH activation of JAK2 recruits the adapter protein SH2B1 to GH/GH receptor/JAK2 complexes where it facilitates GH regulation of the actin cytoskeleton and motility; and 6) SH2B1 is recruited to other receptors in the brain, where it enhances satiety, most likely in part by regulating leptin action and neuronal connections of appetite-regulating neurons. These findings have led to increased understanding of how GH functions, as well as therapeutic interventions for certain cancer and obese individuals, thereby reinforcing the great importance of supporting basic research since one never knows ahead of time what important insight it can provide.
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Affiliation(s)
- Christin Carter-Su
- University of Michigan Medical School, Ann Arbor, Michigan, United States
| | | | - Nadezhda Svezhova
- University of Michigan Medical School, Ann Arbor, Michigan, United States
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15
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Moutabian H, Radi UK, Saleman AY, Adil M, Zabibah RS, Chaitanya MNL, Saadh MJ, Jawad MJ, Hazrati E, Bagheri H, Pal RS, Akhavan-Sigari R. MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition. Pathol Res Pract 2023; 250:154789. [PMID: 37741138 DOI: 10.1016/j.prp.2023.154789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/25/2023]
Abstract
Among the leading causes of death globally has been cancer. Nearly 90% of all cancer-related fatalities are attributed to metastasis, which is the growing of additional malignant growths out of the original cancer origin. Therefore, a significant clinical need for a deeper comprehension of metastasis exists. Beginning investigations are being made on the function of microRNAs (miRNAs) in the metastatic process. Tiny non-coding RNAs called miRNAs have a crucial part in controlling the spread of cancer. Some miRNAs regulate migration, invasion, colonization, cancer stem cells' properties, the epithelial-mesenchymal transition (EMT), and the microenvironment, among other processes, to either promote or prevent metastasis. One of the most well-conserved and versatile miRNAs, miR-155 is primarily distinguished by overexpression in a variety of illnesses, including malignant tumors. It has been discovered that altered miR-155 expression is connected to a number of physiological and pathological processes, including metastasis. As a result, miR-155-mediated signaling pathways were identified as possible cancer molecular therapy targets. The current research on miR-155, which is important in controlling cancer cells' invasion, and metastasis as well as migration, will be summarized in the current work. The crucial significance of the lncRNA/circRNA-miR-155-mRNA network as a crucial regulator of carcinogenesis and a player in the regulation of signaling pathways or related genes implicated in cancer metastasis will be covered in the final section. These might provide light on the creation of fresh treatment plans for controlling cancer metastasis.
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Affiliation(s)
- Hossein Moutabian
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran
| | - Usama Kadem Radi
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Mv N L Chaitanya
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | | | - Ebrahi Hazrati
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Hamed Bagheri
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rashmi Saxena Pal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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16
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Faida P, Attiogbe MKI, Majeed U, Zhao J, Qu L, Fan D. Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cell Signal 2023:110797. [PMID: 37423343 DOI: 10.1016/j.cellsig.2023.110797] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.
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Affiliation(s)
- Paison Faida
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Mawusse K I Attiogbe
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Usman Majeed
- College of Food Science and Technology, Northwest University, Xi'an, Shaanxi 710069, China
| | - Jing Zhao
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
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17
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Yoo HB, Moon JW, Kim HR, Lee HS, Miyabayashi K, Park CH, Ge S, Zhang A, Tae YK, Sub Y, Park HW, Gee HY, Notta F, Tuveson DA, Bang S, Kim MY, Roe JS. A TEAD2-Driven Endothelial-Like Program Shapes Basal-Like Differentiation and Metastasis of Pancreatic Cancer. Gastroenterology 2023; 165:133-148.e17. [PMID: 36907523 PMCID: PMC10330865 DOI: 10.1053/j.gastro.2023.02.049] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 02/18/2023] [Accepted: 02/24/2023] [Indexed: 03/14/2023]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDA), with its highly metastatic propensity, is one of the most lethal subtypes of pancreatic cancer. Although recent large-scale transcriptomic studies have demonstrated that heterogeneous gene expressions play an essential role in determining molecular phenotypes of PDA, biological cues for and consequences of distinct transcriptional programs remain unclear. METHODS We developed an experimental model that enforces the transition of PDA cells toward a basal-like subtype. We combined epigenome and transcriptome analyses with extensive in vitro and in vivo evaluations of tumorigenicity to demonstrate the validity of basal-like subtype differentiation in association with endothelial-like enhancer landscapes via TEA domain transcription factor 2 (TEAD2). Finally, we used loss-of-function experiments to investigate the importance of TEAD2 in regulating reprogrammed enhancer landscape and metastasis in basal-like PDA cells. RESULTS Aggressive characteristics of the basal-like subtype are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of our model. Further, we showed that basal-like subtype PDA cells acquire a TEAD2-dependent proangiogenic enhancer landscape. Genetic and pharmacologic inhibitions of TEAD2 in basal-like subtype PDA cells impair their proangiogenic phenotypes in vitro and cancer progression in vivo. Last, we identify CD109 as a critical TEAD2 downstream mediator that maintains constitutively activated JAK-STAT signaling in basal-like PDA cells and tumors. CONCLUSIONS Our findings implicate a TEAD2-CD109-JAK/STAT axis in the basal-like differentiated pancreatic cancer cells and as a potential therapeutic vulnerability.
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Affiliation(s)
- Hye-Been Yoo
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Jin Woo Moon
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Hwa-Ryeon Kim
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chan Hee Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sabrina Ge
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Amy Zhang
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Yoo Keung Tae
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Yujin Sub
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun-Woo Park
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Heon Yung Gee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea
| | - Faiyaz Notta
- Princess Margaret Cancer Center, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - David A Tuveson
- Lustgarten Foundation Dedicated Laboratory at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Young Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
| | - Jae-Seok Roe
- Department of Biochemistry, Yonsei University, Seoul, Korea.
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18
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Valle-Mendiola A, Gutiérrez-Hoya A, Soto-Cruz I. JAK/STAT Signaling and Cervical Cancer: From the Cell Surface to the Nucleus. Genes (Basel) 2023; 14:1141. [PMID: 37372319 DOI: 10.3390/genes14061141] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/13/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.
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Affiliation(s)
- Arturo Valle-Mendiola
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
| | - Adriana Gutiérrez-Hoya
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
- Cátedra CONACYT, FES Zaragoza, National University of Mexico, Mexico City 09230, Mexico
| | - Isabel Soto-Cruz
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
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19
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Poh AR, Ernst M. Functional roles of SRC signaling in pancreatic cancer: Recent insights provide novel therapeutic opportunities. Oncogene 2023:10.1038/s41388-023-02701-x. [PMID: 37120696 DOI: 10.1038/s41388-023-02701-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/19/2023] [Indexed: 05/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.
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Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC, 3084, Australia.
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20
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Chang R, Dai J, Wang L, Liu H, Jiang H, Liu X, Jiang L, He F, Hu L. PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion. Front Immunol 2023; 14:1061949. [PMID: 37033974 PMCID: PMC10074254 DOI: 10.3389/fimmu.2023.1061949] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 02/28/2023] [Indexed: 03/17/2023] Open
Abstract
IntroductionDysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown.MethodsFirst-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMös) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo.ResultsThe downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMös via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPâ expression in uterine macrophages.DiscussionPlGF plays a key role in early pregnancy maintenance by skewing dMös toward an M2-like phenotype via the FLT-1-STAT3-C/EBP â signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.
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Affiliation(s)
- Ruiqi Chang
- The Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, China
- Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing Medical University, Chongqing, China
| | - Jingcong Dai
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Wang
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Liu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Huanhuan Jiang
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyu Liu
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Linying Jiang
- Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fan He
- The Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, China
- Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing Medical University, Chongqing, China
- *Correspondence: Fan He, ; Lina Hu,
| | - Lina Hu
- The Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, China
- Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing Medical University, Chongqing, China
- *Correspondence: Fan He, ; Lina Hu,
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21
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Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer 2023; 23:115-134. [PMID: 36596870 DOI: 10.1038/s41568-022-00537-3] [Citation(s) in RCA: 106] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 01/04/2023]
Abstract
Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.
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Affiliation(s)
- Yi-Jia Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Andreas Herrmann
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
- Sorrento Therapeutics, San Diego, CA, USA
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
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22
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Chen YH, Hsu JY, Chu CT, Chang YW, Fan JR, Yang MH, Chen HC. Loss of cell-cell adhesion triggers cell migration through Rac1-dependent ROS generation. Life Sci Alliance 2023; 6:6/2/e202201529. [PMID: 36446524 PMCID: PMC9711860 DOI: 10.26508/lsa.202201529] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/30/2022] Open
Abstract
Epithelial cells usually trigger their "migratory machinery" upon loss of adhesion to their neighbors. This default is important for both physiological (e.g., wound healing) and pathological (e.g., tumor metastasis) processes. However, the underlying mechanism for such a default remains unclear. In this study, we used the human head and neck squamous cell carcinoma (HNSCC) SAS cells as a model and found that loss of cell-cell adhesion induced reactive oxygen species (ROS) generation and vimentin expression, both of which were required for SAS cell migration upon loss of cell-cell adhesion. We demonstrated that Tiam1-mediated Rac1 activation was responsible for the ROS generation through NADPH-dependent oxidases. Moreover, the ROS-Src-STAT3 signaling pathway that led to vimentin expression was important for SAS cell migration. The activation of ROS, Src, and STAT3 was also detected in tumor biopsies from HNSCC patients. Notably, activated STAT3 was more abundant at the tumor invasive front and correlated with metastatic progression of HNSCC. Together, our results unveil a mechanism of how cells trigger their migration upon loss of cell-cell adhesion and highlight an important role of the ROS-Src-STAT3 signaling pathway in the progression of HNSCC.
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Affiliation(s)
- Yu-Hsuan Chen
- Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jinn-Yuan Hsu
- Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ching-Tung Chu
- Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yao-Wen Chang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jia-Rong Fan
- Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Muh-Hwa Yang
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hong-Chen Chen
- Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang Ming Chiao Tung University, Taipei, Taiwan .,Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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23
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Wang Y, Lei J, Zhang S, Wang X, Jin J, Liu Y, Gan M, Yuan Y, Sun L, Li X, Han T, Wang JB. 4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer. Cell Death Dis 2022; 13:1075. [PMID: 36575176 PMCID: PMC9794714 DOI: 10.1038/s41419-022-05466-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 12/28/2022]
Abstract
Nutrient-limiting conditions are common during cancer development. The coordination of cellular glucose levels and cell survival is a fundamental question in cell biology and has not been completely understood. 4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation, however, whether 4EBP1 could participate in tumor survival by other mechanism except for translational repression function, especially under glucose starvation conditions remains unknown. Here, we found that protein levels of 4EBP1 was up-regulated in the central region of the tumor which always suffered nutrient deprivation compared with the peripheral region. We further discovered that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions, which prevented 4EBP1 from being targeted for ubiquitin-mediated proteasomal degradation by HERC5. After that, 4EBP1 translocated to cytoplasm and interacted with STAT3 by competing with JAK and ERK, leading to the inactivation of STAT3 in the cytoplasm, resulting in apoptosis under glucose withdrawal conditions. Moreover, 4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis in the central region of tumor. These findings highlight a novel mechanism for 4EBP1 as a new cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions, which was different from its classical function as a translational repressor.
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Affiliation(s)
- Yanan Wang
- grid.412604.50000 0004 1758 4073Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China ,Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang City, 330052 Jiangxi China ,Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang City, 330006 Jiangxi China
| | - Jiapeng Lei
- School of Basic Medical Sciences, Nanchang Medical College, Nanchang City, 330006 Jiangxi China
| | - Song Zhang
- grid.412465.0Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, 310009 Zhejiang China
| | - Xiaomei Wang
- grid.415912.a0000 0004 4903 149XDepartment of Pharmacy, Liaocheng People’s Hospital, Liaocheng City, 252000 Shandong China
| | - Jiangbo Jin
- grid.260463.50000 0001 2182 8825Department of Thoracic Surgery, The First Affifiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China
| | - Yufeng Liu
- grid.260463.50000 0001 2182 8825School of Basic Medical Sciences, Nanchang University, Nanchang City, 330031 Jiangxi China
| | - Mingxi Gan
- grid.260463.50000 0001 2182 8825School of Basic Medical Sciences, Nanchang University, Nanchang City, 330031 Jiangxi China
| | - Yi Yuan
- grid.260463.50000 0001 2182 8825Huankui Academy, Nanchang University, Nanchang City, 330031 Jiangxi China
| | - Longhua Sun
- grid.412604.50000 0004 1758 4073Departments of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China
| | - Xiaolei Li
- grid.412604.50000 0004 1758 4073Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China
| | - Tianyu Han
- grid.412604.50000 0004 1758 4073Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China ,Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang City, 330052 Jiangxi China ,Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang City, 330006 Jiangxi China
| | - Jian-Bin Wang
- grid.260463.50000 0001 2182 8825Department of Thoracic Surgery, The First Affifiliated Hospital of Nanchang University, Nanchang City, 330006 Jiangxi China ,grid.260463.50000 0001 2182 8825School of Basic Medical Sciences, Nanchang University, Nanchang City, 330031 Jiangxi China
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24
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Wong GL, Manore SG, Doheny DL, Lo HW. STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Semin Cancer Biol 2022; 86:84-106. [PMID: 35995341 PMCID: PMC9714692 DOI: 10.1016/j.semcancer.2022.08.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.
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Affiliation(s)
- Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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25
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Pelaz SG, Tabernero A. Src: coordinating metabolism in cancer. Oncogene 2022; 41:4917-4928. [PMID: 36217026 PMCID: PMC9630107 DOI: 10.1038/s41388-022-02487-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 11/08/2022]
Abstract
Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.
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Affiliation(s)
- Sara G Pelaz
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain
| | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
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26
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The JAK-STAT pathway at 30: Much learned, much more to do. Cell 2022; 185:3857-3876. [PMID: 36240739 PMCID: PMC9815833 DOI: 10.1016/j.cell.2022.09.023] [Citation(s) in RCA: 328] [Impact Index Per Article: 109.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/01/2022] [Accepted: 09/14/2022] [Indexed: 11/24/2022]
Abstract
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway arose from investigations of how cells respond to interferons (IFNs), revealing a paradigm in cell signaling conserved from slime molds to mammals. These discoveries revealed mechanisms underlying rapid gene expression mediated by a wide variety of extracellular polypeptides including cytokines, interleukins, and related factors. This knowledge has provided numerous insights into human disease, from immune deficiencies to cancer, and was rapidly translated to new drugs for autoimmune, allergic, and infectious diseases, including COVID-19. Despite these advances, major challenges and opportunities remain.
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27
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Dinakar YH, Kumar H, Mudavath SL, Jain R, Ajmeer R, Jain V. Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors. Life Sci 2022; 309:120996. [PMID: 36170890 DOI: 10.1016/j.lfs.2022.120996] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/13/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern. The JAK-STAT signaling pathway is activated in numerous cancers, including BC. STAT3 is widely involved in BCs, as 40 % of BCs display phosphorylated STAT3. JAK-STAT signaling is crucial for proliferation, survival, metastasis and other cellular events associated with the tumor microenvironment. Hence, targeting this pathway has become an area of interest among researchers. KEY FINDINGS This review article focuses on the role of STAT3 in the initiation, proliferation, progression and metastasis of BC. The roles of various phytochemicals, synthetic molecules and biologicals against JAK-STAT and STAT3 in various cancers have been discussed, with special emphasis on BC. SIGNIFICANCE JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC.
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Affiliation(s)
- Yirivinti Hayagreeva Dinakar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Shyam Lal Mudavath
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali 140306, Punjab, India
| | - Rupshee Jain
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - Ramkishan Ajmeer
- Central Drugs Standard Control Organization, East Zone, Kolkata 700020, West Bengal, India
| | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India.
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Wang H, Man Q, Huo F, Gao X, Lin H, Li S, Wang J, Su F, Cai, L, Shi Y, Liu, B, Bu L. STAT3 pathway in cancers: Past, present, and future. MedComm (Beijing) 2022; 3:e124. [PMID: 35356799 PMCID: PMC8942302 DOI: 10.1002/mco2.124] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/13/2022] [Accepted: 02/21/2022] [Indexed: 12/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.
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Affiliation(s)
- Han‐Qi Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Qi‐Wen Man
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Fang‐Yi Huo
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Xin Gao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Hao Lin
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Su‐Ran Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Jing Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Fu‐Chuan Su
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Lulu Cai,
- Personalized Drug Therapy Key Laboratory of Sichuan ProvinceDepartment of PharmacySchool of MedicineSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Yi Shi
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory MedicineSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Bing Liu,
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Lin‐Lin Bu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
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Zhao Q, Kohut A, Li YJ, Martincuks A, Austria T, Zhang C, Santiago NL, Borrero RM, Phan XT, Melstrom L, Rodriguez-Rodriguez L, Yu H. Niraparib-induced STAT3 inhibition increases its antitumor effects. Front Oncol 2022; 12:966492. [PMID: 36324587 PMCID: PMC9618811 DOI: 10.3389/fonc.2022.966492] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/21/2022] [Indexed: 11/18/2022] Open
Abstract
Recently, poly(ADP-ribosyl)ation polymerase inhibitors (PARPis), which induce synthetic lethality of tumor cells with DNA damage repair defects, have emerged as a promising therapy for ovarian, breast, and pancreatic cancer. Although the PARPi Olaparib is limited to treating cancer patients with DNA repair deficiencies, the PARPi Niraparib is FDA approved to treat ovarian cancer patients regardless of their status in DNA repair pathways. Despite differences in the affinity to PARP enzymes, the rationale behind the clinical use of Niraparib in patients without DNA repair deficiencies is still lacking. Moreover, only Olaparib has been approved for pancreatic ductal adenocarcinoma (PDAC) patients with BRCA mutations, accounting for only 5-7% of total PDACs. It remains unclear whether Niraparib could be beneficial to PDACs without BRCA mutations. We found that Niraparib inhibits ovarian and PDAC tumor cell growth, regardless of BRCA mutational status, more effectively than Olaparib. Unlike Olaparib, which is known to activate STAT3, Niraparib inhibits STAT3 activity in ovarian and PDAC cancer cell lines and patient tumors. Moreover, Niraparib regulates the expression of several STAT3 downstream genes involved in apoptosis. Overexpression of a constitutively activated STAT3 mutant rescues Niraparib-induced cancer cell apoptosis. Our results suggest that Niraparib inhibits pSTAT3 by interfering with SRC tyrosine kinase. Collectively, our studies provide a mechanism underlying Niraparib's ability to induce tumor cell apoptosis without BRCA mutations, suggesting the potential use of Niraparib for treating PDAC patients regardless of BRCA status.
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Affiliation(s)
- Qianqian Zhao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.,Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, United States
| | - Adrian Kohut
- Department of Surgery, Division of Gynecologic Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Yi-Jia Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Theresa Austria
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Nicole Lugo Santiago
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Rosemarie Martinez Borrero
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.,Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, United States
| | - Xuan Thuy Phan
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Laleh Melstrom
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Lorna Rodriguez-Rodriguez
- Department of Surgery, Division of Gynecologic Oncology, City of Hope National Medical Center, Duarte, CA, United States
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
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Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021; 6:402. [PMID: 34824210 PMCID: PMC8617206 DOI: 10.1038/s41392-021-00791-1] [Citation(s) in RCA: 1191] [Impact Index Per Article: 297.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/09/2021] [Accepted: 09/21/2021] [Indexed: 02/08/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.
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Affiliation(s)
- Xiaoyi Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China
| | - Jing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Maorong Fu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Xia Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China.
| | - Wei Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
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Saranyutanon S, Acharya S, Deshmukh SK, Khan MA, Singh S, Singh AP. Nicotine causes alternative polarization of macrophages via Src-mediated STAT3 activation: Potential pathobiological implications. J Cell Physiol 2021; 237:1486-1497. [PMID: 34647621 DOI: 10.1002/jcp.30607] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022]
Abstract
Nicotine is an addictive ingredient of tobacco products and other noncigarette substitutes, including those being used for smoking cessation to relieve withdrawal symptoms. Earlier research, however, has associated nicotine with the risk and poorer outcome of several diseases, including cancer. Macrophages are an important component of the innate immune system and can have both pro-and anti-inflammatory functions depending upon their polarization state. Here, we investigated the effect of nicotine on macrophage polarization, growth, and invasion to understand its role in human physiology. We observed that nicotine induced M2 polarization of RAW264.7 and THP-1-derived macrophages in a dose-dependent manner. Cytokine profiling suggested a mixed M2a/d phenotype of nicotine-polarized macrophages associated with tissue repair and pro-angiogenic functions. Moreover, nicotine treatment also enhanced the growth, motility, and invasion of macrophages. Mechanistic studies revealed increased phosphorylation of STAT3 in nicotine-treated macrophages that was mediated through Src activation. Importantly, pretreatment of macrophages with either Src or STAT3 inhibitor abrogated nicotine-induced macrophage polarization, growth, and motility, suggesting a functional role of the Src-STAT3 signaling axis. Together, our findings reveal a novel role of nicotine in immunosuppression via causing M2 polarization of macrophages that could be implicated in the pathogenesis of various diseases.
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Affiliation(s)
- Sirin Saranyutanon
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
| | - Srijan Acharya
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
| | - Sachin Kumar Deshmukh
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
| | - Mohammad Aslam Khan
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
| | - Seema Singh
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA
| | - Ajay Pratap Singh
- Department of Pathology, University of South Alabama, Mobile, Alabama, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA
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A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte. Int J Mol Sci 2021; 22:ijms22168813. [PMID: 34445513 PMCID: PMC8396041 DOI: 10.3390/ijms22168813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/09/2021] [Accepted: 08/09/2021] [Indexed: 11/17/2022] Open
Abstract
The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human β defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.
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Niu M, Song S, Su Z, Wei L, Li L, Pu W, Zhao C, Ding Y, Wang J, Cao W, Gao Q, Wang H. Inhibition of heat shock protein (HSP) 90 reverses signal transducer and activator of transcription (STAT) 3-mediated muscle wasting in cancer cachexia mice. Br J Pharmacol 2021; 178:4485-4500. [PMID: 34265073 DOI: 10.1111/bph.15625] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/30/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Cancer cachexia is a common cause of death among cancer patients with no currently effective treatment available. In animal models, aberrant activation of STAT3 in skeletal muscle contributes to muscle wasting. However, clinically the factors regulating STAT3 activation and the molecular mechanisms involved remain incompletely understood. EXPERIMENTAL APPROACH The expression of HSP90 and the activation of STAT3 were detected in muscle from the patients with cancer cachexia or the tumour-bearing cachectic mice. HSP90 inhibitors, including 17DMAG (alvespimycin) and PU-H71, were administered to cachexic mice and cachexia parameters, weight loss, food intake, survival rate, body composition, serum metabolites, muscle wasting pathology and catabolic activation were analysed. The co-culture of C2C12 myotube cells with C26 conditioned media was performed to investigate the pathological mechanism involved in catabolic muscle wasting. The roles of HSP90, STAT3 and FOXO1 in myotube atrophy were explored via overexpression or knockdown. RESULTS An enhanced interaction between activated STAT3 and HSP90 in the skeletal muscle of cancer cachexia patients, is a crucial for the development of cachectic muscle wasting. HSP90 inhibitors 17DMAG and PU-H71 alleviated the muscle wasting in C26 and models or the myotube atrophy of C2C12 cells induced by C26 conditional medium. Prolonged STAT3 activation transactivated FOXO1 by binding directly to its promoter and triggered the muscle wasting in a FOXO1-dependent manner in muscle cells. CONCLUSION AND IMPLICATIONS The HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might be a potential therapeutic target for the treatment of cancer cachexia.
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Affiliation(s)
- Mengyuan Niu
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Shiyu Song
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Zhonglan Su
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lulu Wei
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Li Li
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Wenyuan Pu
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Chen Zhao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Yibing Ding
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Jinglin Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Wangsen Cao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Qian Gao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Hongwei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.,State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, China
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Ding X, Lu D, Fan J. A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling. Biosci Biotechnol Biochem 2021; 85:307-314. [PMID: 33604629 DOI: 10.1093/bbb/zbaa007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022]
Abstract
Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.
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Affiliation(s)
- Xiaomin Ding
- Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Jiangsu, China
| | - Danqing Lu
- Department of Orthopedics, The Second People's Hospital of Kunshan, No. 142 Zhongshan Road of Kunshan City, Jiangsu, China
| | - Jianbo Fan
- Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Jiangsu, China
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Liew K, Yu GQS, Wei Pua LJ, Wong LZ, Tham SY, Hii LW, Lim WM, OuYong BM, Looi CK, Mai CW, Fei-Lei Chung F, Tan LP, Ahmad M, Soo-Beng Khoo A, Leong CO. Parallel genome-wide RNAi screens identify lymphocyte-specific protein tyrosine kinase (LCK) as a targetable vulnerability of cell proliferation and chemoresistance in nasopharyngeal carcinoma. Cancer Lett 2021; 504:81-90. [PMID: 33587980 DOI: 10.1016/j.canlet.2021.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/08/2021] [Indexed: 02/05/2023]
Abstract
Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.
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Affiliation(s)
- Kitson Liew
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Gibson Qi Sheng Yu
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Lesley Jia Wei Pua
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia; School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Li Zhe Wong
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Shiau Ying Tham
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Ling-Wei Hii
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia; School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Wei-Meng Lim
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Brian Ming OuYong
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Chin King Looi
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
| | - Chun-Wai Mai
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Felicia Fei-Lei Chung
- Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, Lyon CEDEX 08, France
| | - Lu Ping Tan
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Munirah Ahmad
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia
| | - Alan Soo-Beng Khoo
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam, Selangor, Malaysia; Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia.
| | - Chee-Onn Leong
- Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia; School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
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A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer. J Pers Med 2021; 11:jpm11040262. [PMID: 33916261 PMCID: PMC8066297 DOI: 10.3390/jpm11040262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 11/16/2022] Open
Abstract
Colorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5-10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the SRC gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of SRCV177M resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of paxillin, β-Catenin, and STAT3 mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the SRCV177M variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis.
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Luo Y, Lu Y, Long B, Lin Y, Yang Y, Xu Y, Zhang X, Zhang J. Blocking DNA Damage Repair May Be Involved in Stattic (STAT3 Inhibitor)-Induced FLT3-ITD AML Cell Apoptosis. Front Cell Dev Biol 2021; 9:637064. [PMID: 33796529 PMCID: PMC8007876 DOI: 10.3389/fcell.2021.637064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
The FMS-like tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD) mutation can be found in approximately 25% of all acute myeloid leukemia (AML) cases and is associated with a poor prognosis. The main treatment for FLT3-ITD-positive AML patients includes genotoxic therapy and FLT3 inhibitors, which are rarely curative. Inhibiting STAT3 activity can improve the sensitivity of solid tumor cells to radiotherapy and chemotherapy. This study aimed to explore whether Stattic (a STAT3 inhibitor) affects FLT3-ITD AML cells and the underlying mechanism. Stattic can inhibit the proliferation, promote apoptosis, arrest cell cycle at G0/G1, and suppress DNA damage repair in MV4-11cells. During the process, through mRNA sequencing, we found that DNA damage repair-related mRNA are also altered during the process. In summary, the mechanism by which Stattic induces apoptosis in MV4-11cells may involve blocking DNA damage repair machineries.
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Affiliation(s)
- Yuxuan Luo
- Department of Pediatric, Guangzhou Women and Children's Medical Center, Guangzhou, China.,Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Lu
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Blood Transfusion, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bing Long
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Sen Yat-sen Institute of Hematology, Guangzhou, China
| | - Yansi Lin
- Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanling Yang
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yichuang Xu
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangzhong Zhang
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Sen Yat-sen Institute of Hematology, Guangzhou, China
| | - Jingwen Zhang
- Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Sen Yat-sen Institute of Hematology, Guangzhou, China
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells. Stem Cell Rev Rep 2021; 17:1465-1477. [PMID: 33624208 PMCID: PMC8372029 DOI: 10.1007/s12015-021-10136-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
C3G (RAPGEF1), engaged in multiple signaling pathways, is essential for the early development of the mouse. In this study, we have examined its role in mouse embryonic stem cell self-renewal and differentiation. C3G null cells generated by CRISPR mediated knock-in of a targeting vector exhibited enhanced clonogenicity and long-term self-renewal. They did not differentiate in response to LIF withdrawal when compared to the wild type ES cells and were defective for lineage commitment upon teratoma formation in vivo. Gene expression analysis of C3G KO cells showed misregulated expression of a large number of genes compared with WT cells. They express higher levels of self-renewal factors like KLF4 and ESRRB and show high STAT3 activity, and very low ERK activity compared to WT cells. Reintroduction of C3G expression in a KO line partially reverted expression of ESRRB, and KLF4, and ERK activity similar to that seen in WT cells. The expression of self-renewal factors was persistent for a longer time, and induction of lineage-specific markers was not seen when C3G KO cells were induced to form embryoid bodies. C3G KO cells showed poor adhesion and significantly reduced levels of pFAK, pPaxillin, and Integrin-β1, in addition to downregulation of the cluster of genes involved in cell adhesion, compared to WT cells. Our results show that C3G is essential for the regulation of STAT3, ERK, and adhesion signaling, to maintain pluripotency of mouse embryonic stem cells and enable their lineage commitment for differentiation. ![]()
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Kajiwara K, Yamano S, Aoki K, Okuzaki D, Matsumoto K, Okada M. CDCP1 promotes compensatory renal growth by integrating Src and Met signaling. Life Sci Alliance 2021; 4:4/4/e202000832. [PMID: 33574034 PMCID: PMC7893822 DOI: 10.26508/lsa.202000832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/07/2021] [Accepted: 01/19/2021] [Indexed: 12/15/2022] Open
Abstract
CDCP1 promotes HGF-induced compensatory renal growth by focally and temporally integrating Src and Met-STAT3 signaling in lipid rafts. Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.
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Affiliation(s)
- Kentaro Kajiwara
- Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shotaro Yamano
- Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, Japan
| | - Kazuhiro Aoki
- Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Aichi, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Kunio Matsumoto
- Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Masato Okada
- Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway. Biomedicines 2021; 9:biomedicines9020188. [PMID: 33668421 PMCID: PMC7918075 DOI: 10.3390/biomedicines9020188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 11/18/2022] Open
Abstract
Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL.
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Bittner ML, Lopes R, Hua J, Sima C, Datta A, Wilson-Robles H. Comprehensive live-cell imaging analysis of cryptotanshinone and synergistic drug-screening effects in various human and canine cancer cell lines. PLoS One 2021; 16:e0236074. [PMID: 33544704 PMCID: PMC7864433 DOI: 10.1371/journal.pone.0236074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022] Open
Abstract
Background Several studies have highlighted both the extreme anticancer effects of Cryptotanshinone (CT), a Stat3 crippling component from Salvia miltiorrhiza, as well as other STAT3 inhibitors to fight cancer. Methods Data presented in this experiment incorporates 2 years of in vitro studies applying a comprehensive live-cell drug-screening analysis of human and canine cancer cells exposed to CT at 20 μM concentration, as well as to other drug combinations. As previously observed in other studies, dogs are natural cancer models, given to their similarity in cancer genetics, epidemiology and disease progression compared to humans. Results Results obtained from several types of human and canine cancer cells exposed to CT and varied drug combinations, verified CT efficacy at combating cancer by achieving an extremely high percentage of apoptosis within 24 hours of drug exposure. Conclusions CT anticancer efficacy in various human and canine cancer cell lines denotes its ability to interact across different biological processes and cancer regulatory cell networks, driving inhibition of cancer cell survival.
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Affiliation(s)
- Michael L. Bittner
- Center for Bioinformatics and Genomic Systems Engineering, Texas A&M Engineering Experiment Station, Texas A&M University, College Station, TX, United States of America
- Translational Genomics Research Institute, Phoenix, AZ, United States of America
| | - Rosana Lopes
- Center for Bioinformatics and Genomic Systems Engineering, Texas A&M Engineering Experiment Station, Texas A&M University, College Station, TX, United States of America
- * E-mail: (RL); (HWR)
| | - Jianping Hua
- Center for Bioinformatics and Genomic Systems Engineering, Texas A&M Engineering Experiment Station, Texas A&M University, College Station, TX, United States of America
| | - Chao Sima
- Center for Bioinformatics and Genomic Systems Engineering, Texas A&M Engineering Experiment Station, Texas A&M University, College Station, TX, United States of America
| | - Aniruddha Datta
- Center for Bioinformatics and Genomic Systems Engineering, Texas A&M Engineering Experiment Station, Texas A&M University, College Station, TX, United States of America
| | - Heather Wilson-Robles
- College of Veterinary Medicine, Texas A&M University, College Station, TX, United States of America
- * E-mail: (RL); (HWR)
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Zhai W, Ye X, Wang Y, Feng Y, Wang Y, Lin Y, Ding L, Yang L, Wang X, Kuang Y, Fu X, Eugene Chin Y, Jia B, Zhu B, Ren F, Chang Z. CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner. Br J Cancer 2021; 124:1437-1448. [PMID: 33531691 PMCID: PMC8039031 DOI: 10.1038/s41416-021-01269-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 11/14/2020] [Accepted: 01/05/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. METHODS BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing. RESULTS We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity. CONCLUSIONS We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.
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Affiliation(s)
- Wanli Zhai
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Joint Center for Life Sciences, School of Life Science, Tsinghua University, Beijing, China
| | - Xiongjun Ye
- Urology and Lithotripsy Center, Peking University People's Hospital, Beijing, China
| | - Yinyin Wang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China
| | - Yarui Feng
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China
| | - Ying Wang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China
| | - Yuting Lin
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Joint Center for Life Sciences, School of Life Science, Tsinghua University, Beijing, China
| | - Lidan Ding
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China
| | - Liu Yang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China
| | - Xuning Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Yanshen Kuang
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Xinyuan Fu
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Beijing, China
| | - Y Eugene Chin
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Baoqing Jia
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Bingtao Zhu
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.
| | - Fangli Ren
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.
| | - Zhijie Chang
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.
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Tolomeo M, Cascio A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int J Mol Sci 2021; 22:ijms22020603. [PMID: 33435349 PMCID: PMC7826746 DOI: 10.3390/ijms22020603] [Citation(s) in RCA: 188] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.
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Zhou Y, Chen JJ. STAT3 plays an important role in DNA replication by turning on WDHD1. Cell Biosci 2021; 11:10. [PMID: 33413624 PMCID: PMC7792067 DOI: 10.1186/s13578-020-00524-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that plays a key role in many cellular processes such as cell growth and cancer. However, the functions and mechanisms by which STAT3 regulates cellular processes are not fully understood. RESULTS Here we describe a novel function of STAT3. We demonstrated that STAT3 plays an important role in DNA replication. Specifically, knockdown of STAT3 reduced DNA replication while activation and ectopic expression of STAT3 promoted DNA replication. We further identified the WD repeat and HMG-box DNA-binding protein 1 (WDHD1), which plays an important role in DNA replication initiation, as a novel STAT3 target gene that mediated the DNA replication function of STAT3. We showed that STAT3 bind the promoter/up regulatory region of WDHD1 gene. CONCLUSIONS These studies identified a novel function of STAT3 that is mediated by its newly identified target gene WDHD1 and have important implications.
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Affiliation(s)
- Yunying Zhou
- Medical Research & Laboratory Diagnostic Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Medical Research & Laboratory Diagnostic Center, Central Hospital Affiliated To Shandong First Medical University, Jinan, China.,The Cancer Research Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jason J Chen
- Department of Microbiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,The Cancer Research Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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Luo K, Zhang L, Liao Y, Zhou H, Yang H, Luo M, Qing C. Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review). Oncol Rep 2021; 45:824-834. [PMID: 33432368 PMCID: PMC7859916 DOI: 10.3892/or.2021.7927] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/09/2020] [Indexed: 12/31/2022] Open
Abstract
Epidermal growth factor receptor pathway substrate 8 (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which is involved in cell mitosis, differentiation and other physiological functions. Numerous studies over the last decade have demonstrated that Eps8 is overexpressed in most ubiquitous malignant tumours and subsequently binds with its receptor to activate multiple signalling pathways. Eps8 not only participates in the regulation of malignant phenotypes, such as tumour proliferation, invasion, metastasis and drug resistance, but is also related to the clinicopathological characteristics and prognosis of patients. Therefore, Eps8 is a potential tumour diagnosis and prognostic biomarker and even a therapeutic target. This review aimed to describe the structural characteristics, role and related molecular mechanism of Eps8 in malignant tumours. In addition, the prospect of Eps8 as a target for cancer therapy is examined.
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Affiliation(s)
- Kaili Luo
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Lei Zhang
- Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China
| | - Yuan Liao
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hongyu Zhou
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Hongying Yang
- Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China
| | - Min Luo
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Chen Qing
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Liu Y, Liao S, Bennett S, Tang H, Song D, Wood D, Zhan X, Xu J. STAT3 and its targeting inhibitors in osteosarcoma. Cell Prolif 2020; 54:e12974. [PMID: 33382511 PMCID: PMC7848963 DOI: 10.1111/cpr.12974] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/21/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is one of seven STAT family members involved with the regulation of cellular growth, differentiation and survival. STAT proteins are conserved among eukaryotes and are important for biological functions of embryogenesis, immunity, haematopoiesis and cell migration. STAT3 is widely expressed and located in the cytoplasm in an inactive form. STAT3 is rapidly and transiently activated by tyrosine phosphorylation by a range of signalling pathways, including cytokines from the IL‐6 family and growth factors, such as EGF and PDGF. STAT3 activation and subsequent dimer formation initiates nuclear translocation of STAT3 for the regulation of target gene transcription. Four STAT3 isoforms have been identified, which have distinct biological functions. STAT3 is considered a proto‐oncogene and constitutive activation of STAT3 is implicated in the development of various cancers, including multiple myeloma, leukaemia and lymphomas. In this review, we focus on recent progress on STAT3 and osteosarcoma (OS). Notably, STAT3 is overexpressed and associated with the poor prognosis of OS. Constitutive activation of STAT3 in OS appears to upregulate the expression of target oncogenes, leading to OS cell transformation, proliferation, tumour formation, invasion, metastasis, immune evasion and drug resistance. Taken together, STAT3 is a target for cancer therapy, and STAT3 inhibitors represent potential therapeutic candidates for the treatment of OS.
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Affiliation(s)
- Yun Liu
- Department of Spine and Osteopathic Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.,Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Shijie Liao
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China.,Department of Trauma Orthopedic and Hand Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Samuel Bennett
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Haijun Tang
- Department of Orthopedic, Guangxi hospital for nationalities, Nanning, Guangxi, China
| | - Dezhi Song
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - David Wood
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Xinli Zhan
- Department of Spine and Osteopathic Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.,Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.,Research Centre for Regenerative Medicine, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiake Xu
- Division of Regenerative Biology, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
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Mirzaei S, Gholami MH, Mahabady MK, Nabavi N, Zabolian A, Banihashemi SM, Haddadi A, Entezari M, Hushmandi K, Makvandi P, Samarghandian S, Zarrabi A, Ashrafizadeh M, Khan H. Pre-clinical investigation of STAT3 pathway in bladder cancer: Paving the way for clinical translation. Biomed Pharmacother 2020; 133:111077. [PMID: 33378975 DOI: 10.1016/j.biopha.2020.111077] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Effective cancer therapy requires identification of signaling networks and investigating their potential role in proliferation and invasion of cancer cells. Among molecular pathways, signal transducer and activator of transcription 3 (STAT3) has been of importance due to its involvement in promoting proliferation, and invasion of cancer cells, and mediating chemoresistance. In the present review, our aim is to reveal role of STAT3 pathway in bladder cancer (BC), as one of the leading causes of death worldwide. In respect to its tumor-promoting role, STAT3 is able to enhance the growth of BC cells via inhibiting apoptosis and cell cycle arrest. STAT3 also contributes to metastasis of BC cells via upregulating of MMP-2 and MMP-9 as well as genes in the EMT pathway. BC cells obtain chemoresistance via STAT3 overexpression and its inhibition paves the way for increasing efficacy of chemotherapy. Different molecular pathways such as KMT1A, EZH2, DAB2IP and non-coding RNAs including microRNAs and long non-coding RNAs can function as upstream mediators of STAT3 that are discussed in this review article.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Noushin Nabavi
- Research Services, University of Victoria, Victoria, BC, V8W 2Y2, Canada
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Amirabbas Haddadi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Pooyan Makvandi
- IstitutoItaliano di Tecnologia, Centre for Micro-BioRobotics, viale Rinaldo Piaggio 34, 56025, Pontedera, Pisa, Italy
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey.
| | - Milad Ashrafizadeh
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey; Faculty of Engineering and Natural Sciences, Sabanci University, OrtaMahalle, ÜniversiteCaddesi No. 27, Orhanlı, Tuzla, 34956, Istanbul, Turkey.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200, Pakistan.
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Martincuks A, Li PC, Zhao Q, Zhang C, Li YJ, Yu H, Rodriguez-Rodriguez L. CD44 in Ovarian Cancer Progression and Therapy Resistance-A Critical Role for STAT3. Front Oncol 2020; 10:589601. [PMID: 33335857 PMCID: PMC7736609 DOI: 10.3389/fonc.2020.589601] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/22/2020] [Indexed: 12/15/2022] Open
Abstract
Despite significant progress in cancer therapy over the last decades, ovarian cancer remains the most lethal gynecologic malignancy worldwide with the five-year overall survival rate less than 30% due to frequent disease recurrence and chemoresistance. CD44 is a non-kinase transmembrane receptor that has been linked to cancer metastatic progression, cancer stem cell maintenance, and chemoresistance development via multiple mechanisms across many cancers, including ovarian, and represents a promising therapeutic target for ovarian cancer treatment. Moreover, CD44-mediated signaling interacts with other well-known pro-tumorigenic pathways and oncogenes during cancer development, such as signal transducer and activator of transcription 3 (STAT3). Given that both CD44 and STAT3 are strongly implicated in the metastatic progression and chemoresistance of ovarian tumors, this review summarizes currently available evidence about functional crosstalk between CD44 and STAT3 in human malignancies with an emphasis on ovarian cancer. In addition to the role of tumor cell-intrinsic CD44 and STAT3 interaction in driving cancer progression and metastasis, we discuss how CD44 and STAT3 support the pro-tumorigenic tumor microenvironment and promote tumor angiogenesis, immunosuppression, and cancer metabolic reprogramming in favor of cancer progression. Finally, we review the current state of therapeutic CD44 targeting and propose superior treatment possibilities for ovarian cancer.
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Affiliation(s)
- Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Pei-Chuan Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Qianqian Zhao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Yi-Jia Li
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
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Park J, Lee W, Yun S, Kim SP, Kim KH, Kim JI, Kim SK, Wang KC, Lee JY. STAT3 is a key molecule in the oncogenic behavior of diffuse intrinsic pontine glioma. Oncol Lett 2020; 20:1989-1998. [PMID: 32724445 DOI: 10.3892/ol.2020.11699] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 04/17/2020] [Indexed: 11/06/2022] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is one of the most lethal childhood brain tumors. This tumor is unique because it is detected exclusively in the ventral pons of patients aged between 6 and 7 years, which suggests a developmental nature of its formation. Signal transducer and activator of transcription 3 (STAT3) is a critical molecule for the differentiation of neural stem cells into astrocytes during neurodevelopment. Additionally, STAT3 is associated with oncogenesis and the epithelial-mesenchymal transition (EMT) in various types of tumor. In recent years, several studies have demonstrated the oncogenic role of STAT3 in high-grade gliomas. However, the role of STAT3 in DIPG at the cellular level remains unknown. To assess the possible association between gliogenesis and DIPG, the expression levels of various molecules participating in the differentiation of neural stem cells were compared between normal brain control tissues and DIPG tissues using open public data. All of the screened genes exhibited significantly increased expression in DIPG tissues compared with normal tissues. As STAT3 expression was the most increased, the effect of STAT3 inhibition in a DIPG cell line was assessed via STAT3 short hairpin (sh)RNA transfection and treatment with AG490, a STAT3 inhibitor. Changes in viability, apoptosis, EMT and radiation therapy efficiency were also evaluated. Downregulation of STAT3 resulted in decreased cyclin D1 expression and cell viability, migration and invasion. Additionally, treatment with STAT3 shRNA or AG490 suppressed the EMT phenotype. Finally, when radiation was administered in combination with STAT3 inhibition, the therapeutic efficiency, assessed by cell viability and DNA damage repair, was increased. The present results suggest that STAT3 is a potential therapeutic target in DIPG, especially when combined with radiation therapy.
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Affiliation(s)
- Jinju Park
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Woochan Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sangil Yun
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Saet Pyoul Kim
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kyung Hyun Kim
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Republic of Korea
| | - Jong-Il Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Seung-Ki Kim
- Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Republic of Korea
| | - Kyu-Chang Wang
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Republic of Korea
| | - Ji Yeoun Lee
- Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Republic of Korea
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