|
1
|
Lara B, Snyder M, Fimbres J, Yang E, Song G, Duggineni VK, Wang Z, Sherr DH. The AhR regulates IFN-induced immune checkpoints in lung cancer cells through HNRNPH1, an RNA-binding protein, and INCR1, a novel long non-coding RNA. J Biol Chem 2025:110316. [PMID: 40449595 DOI: 10.1016/j.jbc.2025.110316] [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: 11/26/2024] [Revised: 04/28/2025] [Accepted: 05/17/2025] [Indexed: 06/03/2025] Open
Abstract
Although immune checkpoint inhibitors show great promise, not all patients respond and many do not achieve durable responses. Consequently, further investigations into potentially targetable molecules that regulate immune checkpoints are warranted. Previous studies in several cancers demonstrated that interferons produced by tumor-infiltrating leukocytes regulate immunosuppressive PD-L1, PD-L2 and IDO1 through JAK/STAT signaling. Here, we investigated a novel role for an immunosuppressive environmental chemical receptor, previously implicated in smoking-related cancers, in IFN signaling in human lung adenocarcinoma (LUAD) cells. Deletion of the aryl hydrocarbon receptor (AhR) from A549 LUAD cells significantly decreased baseline JAK2, STAT1, STAT3, IRF1 (a JAK/STAT target), PD-L1, PD-L2, and IDO1 expression. IFNγ and IFNα increased expression of JAK/STAT and immune checkpoint genes and proteins, but these increases were significantly diminished or absent in AhR-knockout cells. The AhR similarly controls IFN-induced, JAK/STAT-driven increases in multiple MHC class I- and class II-related genes. AhR control of type I and type II interferon signaling is mediated through up-regulation of a lncRNA, the IFN-stimulated non-coding RNA 1 (INCR1), and through repression of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), which sequesters JAK/STAT-related and immune checkpoint gene transcripts. The data suggest that the AhR is a key mediator of tumor immunosuppression through regulation of IFN-induced INCR1 and JAK/STAT signaling and, thereby, expression of immune checkpoints. However, that immunosuppression may be tempered by AhR control of MHC expression. Given the multiple roles of JAK/STAT signaling in the immune system, the results also suggest multiple levels on which the AhR may affect tumor immunity.
Collapse
Affiliation(s)
- Brian Lara
- Department of Environmental Health, Boston University School of Public Health
| | | | - Jocelyn Fimbres
- Department of Environmental Health, Boston University School of Public Health
| | - Eric Yang
- Department of Environmental Health, Boston University School of Public Health
| | - Gang Song
- Department of Environmental Health, Boston University School of Public Health
| | | | - Zhongyan Wang
- Department of Environmental Health, Boston University School of Public Health
| | - David H Sherr
- Department of Environmental Health, Boston University School of Public Health.
| |
Collapse
|
|
2
|
Hong Y, He J, Deng D, Liu Q, Zu X, Shen Y. Targeting kinases that regulate programmed cell death: a new therapeutic strategy for breast cancer. J Transl Med 2025; 23:439. [PMID: 40229646 PMCID: PMC11995514 DOI: 10.1186/s12967-025-06367-9] [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: 12/09/2024] [Accepted: 03/08/2025] [Indexed: 04/16/2025] Open
Abstract
Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.
Collapse
Affiliation(s)
- Yun Hong
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jun He
- Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, China
| | - Dan Deng
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qinyue Liu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
- Hunan Provincial Clinical Medical Research Center for Drug Evaluation of major chronic diseases, Hengyang, China.
| | - Yingying Shen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
- Hunan Provincial Clinical Medical Research Center for Drug Evaluation of major chronic diseases, Hengyang, China.
| |
Collapse
|
|
3
|
Ma Z, Mu R, Zhou Z, Hu Z, Shen M, Lu C, Wang H, Zhang C, Zhang M, Yi Z, Deng Z, Zhao Y, Zhu J, Wen G, Jin H, An J, Tuo B, Liu X, Li T. The mammalian acid chitinase promotes oncogenic properties of thyroid cancer cells through the JAK2/STAT3 pathway. Eur Thyroid J 2025; 14:e240311. [PMID: 40198658 PMCID: PMC12053917 DOI: 10.1530/etj-24-0311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/07/2025] [Accepted: 04/08/2025] [Indexed: 04/10/2025] Open
Abstract
Objective Mammalian acid chitinase (AMCase; CHIA) has potential as a biomarker and drug target in the fields of medicine and pharmacology, and its role in inhibiting tumor growth and Th2 cell-mediated asthma-related inflammation has become a research hotspot. However, the role of CHIA in thyroid cancer is unclear. Methods Tissue microarrays and thyroid cancer cell lines were used to detect CHIA expression and determine its clinical relevance. CHIA gene expression was altered in thyroid cancer cells to examine the effects of CHIA expression on the biological behavior of thyroid cancer cells, and the related molecular mechanisms involved were explored. Results We first examined CHIA expression in a thyroid tissue microarray using immunohistochemistry. We found that CHIA was significantly upregulated in thyroid cancer tissues relative to paired thyroid cancer adjacent tissues. After correlation analysis, we found that upregulated CHIA expression correlated with the tumor-node-metastasis (TNM) stage of patients with thyroid cancer. Similarly, CHIA expression was significantly higher in the thyroid cancer cell lines BCPAP, TPC-1, KTC-1 and FTC133 than in the human normal thyroid epithelial cell line Nthy-ori-3-1. CHIA promotes proliferation, migration and invasion; inhibits thyroid cancer cell apoptosis; and regulates markers of proliferation and epithelial-mesenchymal transition. Mechanistically, CHIA activated the JAK2/STAT3 signaling pathway in thyroid cancer cells. Conclusions CHIA upregulation promoted the proliferation, migration and invasion of thyroid cancer cells through JAK2/STAT3 signaling pathway activation. Therefore, CHIA could represent a potential new oncoprotein for patients with thyroid cancer.
Collapse
Affiliation(s)
- Zhiyuan Ma
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Renmin Mu
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhengxing Zhou
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zilai Hu
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Mimi Shen
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Chengli Lu
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hu Wang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Chengmin Zhang
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Minglin Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zilin Deng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yingying Zhao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| |
Collapse
|
|
4
|
Saito R, Fukushima M, Sasaki M, Okamoto A, Ogiwara H. Targeting USP8 causes synthetic lethality through degradation of FGFR2 in ARID1A-deficient ovarian clear cell carcinoma. NPJ Precis Oncol 2025; 9:69. [PMID: 40074856 PMCID: PMC11903656 DOI: 10.1038/s41698-025-00850-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Over half of ovarian clear cell carcinoma (OCCC) cases exhibit deficiencies in the ARID1A gene, a chromatin remodeling complex component. OCCC is resistant to chemotherapy and challenging to treat, necessitating new drug treatment strategies. This study used a publicly available dependency factor database to identify synthetic lethal targets for ARID1A-deficient cancer. The DepMap portal was used to identify genes on which ARID1A-deficient cancer cell lines are highly dependent. Our analysis limited to ovarian cancer cell lines only identified the deubiquitinating enzyme USP8 as a synthetic lethal target in ARID1A-deficient OCCC cancer cell lines and mouse xenograft models. In addition, USP8 inhibitors were more selective for ARID1A-deficient cells than existing candidate drugs used in promising clinical trials for ARID1A-deficient cancers. Suppression of USP8 in ARID1A-deficient cells led to degradation of FGFR2 via the proteasome. Deficiency of ARID1A causes abnormalities in the STAT3 pathway, which is one of the downstream pathways of FGFR2, but suppression of USP8 attenuates phosphorylation of STAT3 pT705 and induces apoptosis. Taken together, our data suggest that USP8 is a novel therapeutic target for ARID1A-deficient OCCC and that USP8 inhibitors suppress FGFR2-STAT3 signaling.
Collapse
Affiliation(s)
- Ryosuke Saito
- Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan
| | - Makoto Fukushima
- Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
| | - Mariko Sasaki
- Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan
| | - Hideaki Ogiwara
- Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan.
| |
Collapse
|
|
5
|
Mahmoud MO, Al-Hamid HA, Hassan NF, El-Ansary MR, Gomaa SB. Linagliptin Mitigates DMH-Induced Colorectal Cancer in Rats: Crosstalk Between NFAT and IL-6/JAK2/STAT3/NF-κB Signaling Hubs. J Biochem Mol Toxicol 2025; 39:e70206. [PMID: 40070168 DOI: 10.1002/jbt.70206] [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: 09/07/2024] [Revised: 01/30/2025] [Accepted: 03/02/2025] [Indexed: 05/13/2025]
Abstract
Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each; normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-κB signaling cascades.
Collapse
Affiliation(s)
- Mohamed O Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Hager Abd Al-Hamid
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Noha F Hassan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Safaa B Gomaa
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| |
Collapse
|
|
6
|
Hosseini F, Ahmadi A, Sarvi ZN, Iranshahi M, Rassouli FB. 7-Geranyloxycoumarin modulated metastatic potential of osteosarcoma cells via interaction with MMPs and JAK1/2. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03847-z. [PMID: 39954065 DOI: 10.1007/s00210-025-03847-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/23/2025] [Indexed: 02/17/2025]
Abstract
Osteosarcoma (OS) is a highly aggressive bone cancer that primarily affects young adults. The tumor microenvironment and molecular mediators, including Janus kinases (JAKs) and matrix metalloproteinases (MMPs), significantly influence OS metastasis; activation of the JAK/STAT pathway enhances MMP expression and activity, promoting OS metastasis. 7-Geranyloxycoumarin, a natural agent found in various edible fruits and vegetables, possesses valuable pharmaceutical activities. This study aimed to investigate the effects of 7-geranyloxycoumarin on the metastasis of OS cells for the first time. To achieve this, a protein-protein interaction (PPI) network was constructed from the potential molecular and pathogenic targets associated with 7-geranyloxycoumarin and OS to identify overlapping targets. Subsequently, GO and KEGG pathway enrichment analyses were conducted. Molecular docking and dynamic simulations were also performed to elucidate the binding affinity of 7-geranyloxycoumarin with JAK1 and JAK2. For in vitro studies, 7-geranyloxycoumarin was first extracted from Ferula szowitsiana using thin-layer chromatography. The cells were then treated and evaluated for viability, apoptosis, migration, invasion, adhesion, and MMPs activity. The study identified 50 shared targets and revealed MMP-2, MMP-9, JAK1, and JAK2 as hub genes, confirmed through enrichment analyses. Molecular docking revealed strong interactions between 7-geranyloxycoumarin and JAK1 and JAK2 proteins, and molecular dynamics simulations indicated both conformational flexibility and binding stability of the ligand-protein complex. Moreover, experimental studies demonstrated that 7-geranyloxycoumarin did not induce apoptosis but significantly altered the migration, invasion, and adhesion of OS cells by inhibiting the activity of MMPs. In conclusion, 7-geranyloxycoumarin is proposed as a promising therapeutic agent for targeting metastasis in OS cells.
Collapse
Affiliation(s)
- Fatemehsadat Hosseini
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Abdolreza Ahmadi
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Zahra Nasiri Sarvi
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
| |
Collapse
|
|
7
|
Caputo L, Stamenkovic C, Tierney MT, Falzarano MS, Bassel-Duby R, Ferlini A, Olson EN, Puri PL, Sacco A. Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.09.624203. [PMID: 39713478 PMCID: PMC11661153 DOI: 10.1101/2024.12.09.624203] [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: 12/24/2024]
Abstract
Generation of in vitro induced pluripotent cells (hiPSCs)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, as for example Duchenne Muscular Dystrophy (DMD). Multiple approaches, involving ectopic expression of key regulatory myogenic genes or small molecules cocktails, have been described by different groups to obtain SMPC towards cell-transplantation in vivo as a therapeutic approach to skeletal muscle diseases. However, hiPSCs-derived SMPC generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation. Here we demonstrate that modulation of the JAK2/STAT3 signaling pathway during an in vitro skeletal muscle differentiation protocol, increases the yield of PAX7+ and CD54+ SMPCs and drive them to a postnatal maturation stage, in both human ES and patient-derived iPSCs. Importantly, upon removal of the inhibition from the cultures, the obtained SMPCs are able to differentiate into multinucleated myotubes in vitro. These findings reveal that modulation of the JAK2/STAT3 signaling pathway is a potential therapeutic avenue to generate SMPCs in vitro with increase potential for cell-therapy approaches.
Collapse
Affiliation(s)
- Luca Caputo
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA
| | - Cedomir Stamenkovic
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Matthew T. Tierney
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | | | - Rhonda Bassel-Duby
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | | | - Eric N. Olson
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Pier Lorenzo Puri
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA
| | - Alessandra Sacco
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, La Jolla, CA 92037, USA
| |
Collapse
|
|
8
|
Sangseekew W, Ornnork N, Sornprachum T, Sirirak J, Lirdprapamongkol K, Boonsombat J, Svasti J, Keeratichamroen S. Unraveling the mechanism of the anticancer potential of emodin using 2D and spheroid models of A549 cells. Biochem Biophys Res Commun 2024; 736:150908. [PMID: 39476760 DOI: 10.1016/j.bbrc.2024.150908] [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: 08/15/2024] [Revised: 10/15/2024] [Accepted: 10/25/2024] [Indexed: 11/10/2024]
Abstract
The increasing global cancer burden necessitates the development of new treatment options. Herbal medicine offers a viable alternative to conventional cancer treatments. Numerous studies have shown that 3-dimensional (3D) cell culture more accurately represents tumor characteristics in vivo. Therefore, this study utilized tumor spheroids to explore the therapeutic efficacy of emodin, a natural product-derived bioactive agent. We investigated differences in chemotherapeutic response between A549 cells cultured in 2D versus spheroids, assessing key factors influencing cancer progression, including apoptosis, cell proliferation, cell cycle, migration and invasion. The findings revealed that spheroid cells displayed increased resistance to emodin compared to cells cultured in 2D. Emodin exhibited a more pronounced cytostatic effect in 2D cells, while its cytotoxic effect was more prominent in spheroid cells. Moreover, emodin treatment diminished the migratory and invasive capabilities of the cells. Mechanistic investigations indicated that emodin triggered apoptosis in A549 cells via the mitochondrial apoptotic pathway. Emodin-treated cells exhibited a significant reduction in the phosphorylation of key cancer progression pathways, including JAK2, STAT3, FAK, and ERK, compared to untreated controls. Molecular docking analysis confirmed the interactions of emodin with JAK2 and FAK. These findings suggest that the JAK2/STAT3 and FAK/ERK signaling pathways may serve as critical drivers of the therapeutic effectiveness of emodin in A549 cells.
Collapse
Affiliation(s)
- Wannapa Sangseekew
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Narittira Ornnork
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Thiwaree Sornprachum
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Jitnapa Sirirak
- Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom, 73000, Thailand
| | - Kriengsak Lirdprapamongkol
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, Bangkok, 10400, Thailand
| | - Jutatip Boonsombat
- Laboratory of Natural Products, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Jisnuson Svasti
- Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, 10210, Thailand; Applied Biological Sciences Program, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand
| | | |
Collapse
|
|
9
|
Fasouli ES, Katsantoni E. Age-associated myeloid malignancies - the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia. FEBS Lett 2024; 598:2809-2828. [PMID: 39048534 PMCID: PMC11586607 DOI: 10.1002/1873-3468.14985] [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: 03/16/2024] [Revised: 06/08/2024] [Accepted: 06/17/2024] [Indexed: 07/27/2024]
Abstract
In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age-related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non-malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK-STAT pathway in age-associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age-related disorders.
Collapse
Affiliation(s)
- Eirini Sofia Fasouli
- Biomedical Research FoundationAcademy of Athens, Basic Research CenterAthensGreece
| | - Eleni Katsantoni
- Biomedical Research FoundationAcademy of Athens, Basic Research CenterAthensGreece
| |
Collapse
|
|
10
|
Suzauddula M, Kobayashi K, Park S, Sun XS, Wang W. Bioengineered Anthocyanin-Enriched Tomatoes: A Novel Approach to Colorectal Cancer Prevention. Foods 2024; 13:2991. [PMID: 39335919 PMCID: PMC11430996 DOI: 10.3390/foods13182991] [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: 08/10/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health challenge, with barriers to effective prevention and treatment including tumor recurrence, chemoresistance, and limited overall survival rates. Anthocyanins, known for their strong anti-cancer properties, have shown promise in preventing and suppressing various cancers, including CRC. However, natural sources of anthocyanins often fail to provide sufficient quantities needed for therapeutic effects. Bioengineered crops, particularly anthocyanin-enriched tomatoes, offer a viable solution to enhance anthocyanin content. Given its large-scale production and consumption, tomatoes present an ideal target for bioengineering efforts aimed at increasing dietary anthocyanin intake. This review provides an overview of anthocyanins and their health benefits, elucidating the mechanisms by which anthocyanins modulate the transcription factors involved in CRC development. It also examines case studies demonstrating the successful bioengineering of tomatoes to boost anthocyanin levels. Furthermore, the review discusses the effects of anthocyanin extracts from bioengineered tomatoes on CRC prevention, highlighting their role in altering metabolic pathways and reducing tumor-related inflammation. Finally, this review addresses the challenges associated with bioengineering tomatoes and proposes future research directions to optimize anthocyanin enrichment in tomatoes.
Collapse
Affiliation(s)
- Md Suzauddula
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Kaori Kobayashi
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| | - Sunghun Park
- Department of Horticulture and Nature Resources, Kansas State University, Manhattan, KS 66506, USA;
| | - Xiuzhi Susan Sun
- Department of Grain Science and Industry, Kansas State University, Manhattan, KS 66506, USA;
| | - Weiqun Wang
- Department of Food Nutrition Dietetics and Health, Kansas State University, Manhattan, KS 66506, USA; (M.S.); (K.K.)
| |
Collapse
|
|
11
|
Baars MJ, Floor E, Sinha N, ter Linde JJ, van Dam S, Amini M, Nijman IJ, ten Hove JR, Drylewicz J, Offerhaus GA, Laclé MM, Oldenburg B, Vercoulen Y. Multiplex spatial omics reveals changes in immune-epithelial crosstalk during inflammation and dysplasia development in chronic IBD patients. iScience 2024; 27:110550. [PMID: 39165839 PMCID: PMC11334790 DOI: 10.1016/j.isci.2024.110550] [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: 11/30/2023] [Revised: 05/16/2024] [Accepted: 07/16/2024] [Indexed: 08/22/2024] Open
Abstract
Patients with long-standing inflammatory bowel disease (IBD) face an increased risk of developing colitis-associated cancer (CAC). Although IBD-induced prolonged inflammation seems to be involved in CAC pathogenesis, the specific molecular changes that contribute remain unknown. Here, we applied digital spatial RNA profiling, RNAscope, and imaging mass cytometry to examine paired uninflamed, inflamed, and early dysplastic mucosa of patients with IBD. We observed robust type 3 (IL-17) responses during inflammation, accompanied by elevated JAK-STAT signaling and phosphorylated STAT3 (P-STAT3) levels, with both inflamed and dysplastic mucosa displaying immune cell activation. Higher stromal P-STAT3 was detected in uninflamed and inflamed mucosa of patients who eventually developed dysplasia. CD8a+ T cells did not infiltrate inflamed or dysplastic epithelial regions in these patients, while control patients showed elevated CD8a in inflamed mucosa. Our study reveals distinct inflammatory patterns throughout CAC development, marked by an activated IL-17 pathway, engaged STAT3, and diminished cytotoxic T cell infiltration.
Collapse
Affiliation(s)
- Matthijs J.D. Baars
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
| | - Evelien Floor
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Neeraj Sinha
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
| | - José J.M. ter Linde
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Stephanie van Dam
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Mojtaba Amini
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
- UCyTOF, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
| | - Isaäc J. Nijman
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
- USEQ, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
| | - Joren R. ten Hove
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Julia Drylewicz
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, EA, Utrecht 3584, the Netherlands
| | - G.Johan A. Offerhaus
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Miangela M. Laclé
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
| | - Yvonne Vercoulen
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
- UCyTOF, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
| |
Collapse
|
|
12
|
Siragusa G, Tomasello L, Giordano C, Pizzolanti G. Survivin (BIRC5): Implications in cancer therapy. Life Sci 2024; 350:122788. [PMID: 38848940 DOI: 10.1016/j.lfs.2024.122788] [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: 01/26/2024] [Revised: 03/13/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
Inhibitors of Apoptosis proteins (IAPs) were discovered through experiments aimed at rescuing apoptosis in insects. Classically associated with the inhibition of apoptosis, the IAP member Survivin also regulates cell cycle progression and is an essential component of the Chromosomal Passenger Complex (CPC), responsible for chromosomal segregation. Although undetectable in most adult tissues, Survivin is expressed in Adult Stem Cells (ASCs) and plays a crucial role in their maintenance. Survivin is overexpressed in most cancers, contributing to their clonal expansion. As a result, it has been proposed as a possible anticancer target for nearly two decades. In this discussion, we will explore the rationale behind Survivin as a therapeutic target, focusing on common cancer types such as carcinomas, sarcomas, and leukemias. We will delve into the modulation of Survivin by cancer pro-survival cell signaling, the association between SNPs and tumorigenesis, and its regulation by miRNAs. Finally, we will compare cell growth, clonogenic capacity, and apoptosis, along with different strategies for Survivin inhibition, including gene expression and protein activity modulation.
Collapse
Affiliation(s)
- Giuseppe Siragusa
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Laura Tomasello
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Carla Giordano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Giuseppe Pizzolanti
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy; Advanced Technologies Network Center (ATEN Center), University of Palermo, Italy.
| |
Collapse
|
|
13
|
Xu Y, Yang T, Xu Q, Tang Y, Yang Q. Vesicle-associated membrane protein 8 knockdown exerts anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on colorectal cancer cells by inhibition of the JAK/STAT3 pathway. J Bioenerg Biomembr 2024; 56:419-431. [PMID: 38720136 DOI: 10.1007/s10863-024-10019-w] [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: 03/14/2024] [Accepted: 04/20/2024] [Indexed: 07/03/2024]
Abstract
Vesicle-associated membrane protein 8 (VAMP8), a soluble n-ethylmaleimide-sensitive factor receptor protein, acts as an oncogenic gene in the progression of several malignancies. Nevertheless, the roles and mechanisms of VAMP8 in colorectal cancer (CRC) progression remain unknown. The expression and prognostic significance of VAMP8 in CRC samples were analyzed through bioinformatics analyses. Cell proliferation was detected using CCK-8 and EdU incorporation assays and apoptosis was evaluated via flow cytometry. Western blot analysis was conducted to examine the protein expression. Ferroptosis was evaluated by measurement of iron metabolism, lipid peroxidation, and glutathione (GSH) content. VAMP8 was increased in CRC samples relative to normal samples on the basis of GEPIA and HPA databases. CRC patients with high level of VAMP8 had a worse overall survival. VAMP8 depletion led to a suppression of proliferation and promotion of apoptosis in CRC cells. Additionally, VAMP8 knockdown suppressed beclin1 expression and LC3-II/LC3-I ratio, elevated p62 expression, increased Fe2+, labile iron pool, lipid reactive oxygen species, and malondialdehyde levels, and repressed GSH content and glutathione peroxidase activity. Moreover, VAMP8 knockdown inhibited the activation of janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in CRC cells. Mechanistically, activation of the JAK/STAT3 pathway by JAK1 or JAK2 overexpression attenuated VAMP8 silencing-mediated anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on CRC cells. In conclusion, VAMP8 knockdown affects the proliferation, apoptosis, autophagy, and ferroptosis by the JAK/STAT3 pathway in CRC cells.
Collapse
Affiliation(s)
- Yi Xu
- Department of General Surgery, Nanyang First People's Hospital, Nanyang, China
| | - Tianyao Yang
- Department of General Surgery, Tiantai People's Hospital of Zhejiang Province, Taizhou, China
| | - Qiu Xu
- Department of Thyroid and Breast Surgery, Nanyang First People's Hospital, Nanyang, China
- Nanyang Key Laboratory of Thyroid Tumor Prevention and Treatment, Nanyang First People's Hospital, Nanyang, China
| | - Yan Tang
- Department of General Surgery, Nanyang First People's Hospital, Nanyang, China
| | - Qiong Yang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
| |
Collapse
|
|
14
|
Esmaeili N, Bakheet A, Tse W, Liu S, Han X. Interaction of the intestinal cytokines-JAKs-STAT3 and 5 axes with RNA N6-methyladenosine to promote chronic inflammation-induced colorectal cancer. Front Oncol 2024; 14:1352845. [PMID: 39136000 PMCID: PMC11317299 DOI: 10.3389/fonc.2024.1352845] [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: 12/09/2023] [Accepted: 06/25/2024] [Indexed: 08/15/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians' most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro-oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers.
Collapse
Affiliation(s)
- Nardana Esmaeili
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Ahmed Bakheet
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - William Tse
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Shujun Liu
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
| | - Xiaonan Han
- Division of Hematology and Oncology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU) School of Medicine, Cleveland, OH, United States
- Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University (CWRU), Cleveland, OH, United States
| |
Collapse
|
|
15
|
He W, Li ZQ, Gu HY, Pan QL, Lin FX. Targeted Therapy of Spinal Cord Injury: Inhibition of Apoptosis Is a Promising Therapeutic Strategy. Mol Neurobiol 2024; 61:4222-4239. [PMID: 38066400 DOI: 10.1007/s12035-023-03814-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/16/2023] [Indexed: 07/11/2024]
Abstract
Spinal cord injury (SCI) is a serious disabling central nervous system injury that can lead to motor, sensory, and autonomic dysfunction below the injury level. SCI can be divided into primary injury and secondary injury according to pathological process. Primary injury is mostly irreversible, while secondary injury is a dynamic regulatory process. Apoptosis is an important pathological event of secondary injury and has a significant effect on the recovery of nerve function after SCI. Nerve cell death can further aggravate the microenvironment of the injured site, leading to neurological dysfunction and thus affect the clinical outcome of patients. Therefore, apoptosis plays a crucial role in the pathological progression of secondary SCI, while inhibiting apoptosis may be a promising therapeutic strategy for SCI. This review will summarize and explore the factors that lead to cell death after SCI, the influence of cross talk between signaling pathways and pathways involved in apoptosis and discuss the influence of apoptosis on SCI, and the therapeutic significance of targeting apoptosis on SCI. This review helps us to understand the role of apoptosis in secondary SCI and provides a theoretical basis for the treatment of SCI based on apoptosis.
Collapse
Affiliation(s)
- Wei He
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Zhi-Qiang Li
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Hou-Yun Gu
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Qi-Lin Pan
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China
| | - Fei-Xiang Lin
- Department of Spine Surgery, Ganzhou People's Hospital, Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China.
- Department of Spine Surgery, The Affiliated Ganzhou Hospital of Nanchang University (Ganzhou Hospital-Nanfang Hospital, Southern Medical University), Jiangxi Province, 16 Meiguan Avenue, Ganzhou, 341000, People's Republic of China.
| |
Collapse
|
|
16
|
Chowdhury R, Bhuia MS, Wilairatana P, Afroz M, Hasan R, Ferdous J, Rakib AI, Sheikh S, Mubarak MS, Islam MT. An insight into the anticancer potentials of lignan arctiin: A comprehensive review of molecular mechanisms. Heliyon 2024; 10:e32899. [PMID: 38988539 PMCID: PMC11234030 DOI: 10.1016/j.heliyon.2024.e32899] [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: 02/13/2024] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 07/12/2024] Open
Abstract
Natural products are being developed as possible treatment options due to the rising prevalence of cancer and the harmful side effects of synthetic medications. Arctiin is a naturally occurring lignan found in numerous plants and exhibits different pharmacological activities, along with cancer. To elucidate the anticancer properties and underlying mechanisms of action, a comprehensive search of various electronic databases was conducted using appropriate keywords to identify relevant publications. The findings suggest that arctiin exhibits anticancer properties against tumor formation and various cancers such as cervical, myeloma, prostate, endothelial, gastric, and colon cancers in several preclinical pharmacological investigations. This naturally occurring compound exerts its anticancer effect through different cellular mechanisms, including mitochondrial dysfunction, cell cycle at different phases (G2/M), inhibition of cell proliferation, apoptotic cell death, and cytotoxic effects, as well as inhibition of migration and invasion of various malignant cells. Moreover, the study also revealed that, among the various cellular pathways, arctiin was shown to be more potent in terms of the PI3K/AKT and JAK/STAT signaling pathways. However, pharmacokinetic investigation indicated the compound's poor oral bioavailability. Because of these findings, arctiin might be considered a promising chemotherapeutic drug candidate.
Collapse
Affiliation(s)
- Raihan Chowdhury
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | - Md. Shimul Bhuia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Meher Afroz
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | - Rubel Hasan
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | - Jannatul Ferdous
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
| | - Asraful Islam Rakib
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | - Salehin Sheikh
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
| | | | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
- Phytochemistry and Biodiversity Research Laboratory, BioLuster Research Center, Gopalganj 8100, Dhaka, Bangladesh
- Pharmacy Discipline, Khulna University, Khulna 9208, Bangladesh
| |
Collapse
|
|
17
|
Abstract
This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.
Collapse
Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Ju Hu
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Liang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Cai-Yun He
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Dong Wan
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yu-Qi Huang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Can-Hua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hong Wu
- State Key Laboratory of Powder Metallurgy, Central South University, Changsha 410083, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
18
|
Duan ZD, Zheng LY, Jia QY, Chen HL, Xu DY, Yang YJ, Qi Z, Yang L, Wu CY. Effect of scutellarin on BV-2 microglial-mediated apoptosis in PC12 cells via JAK2/STAT3 signalling pathway. Sci Rep 2024; 14:13430. [PMID: 38862696 PMCID: PMC11166921 DOI: 10.1038/s41598-024-64226-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: 02/23/2024] [Accepted: 06/06/2024] [Indexed: 06/13/2024] Open
Abstract
Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However, whether scutellarin regulates activated microglia-mediated neuronal apoptosis and its mechanisms remains unclear. This study aimed to investigate whether scutellarin can attenuate PC12 cell apoptosis induced by activated microglia via the JAK2/STAT3 signalling pathway. Microglia were cultured in oxygen-glucose deprivation (OGD) medium, which acted as a conditioning medium (CM) to activate PC12 cells, to investigate the expression of apoptosis and JAK2/STAT3 signalling-related proteins. We observed that PC12 cells apoptosis in CM was significantly increased, the expression and fluorescence intensity of the pro-apoptotic protein Bax and apoptosis-related protein cleaved caspase-3 were increased, and expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) was decreased. Phosphorylation levels and fluorescence intensity of the JAK2/STAT3 signalling pathway-related proteins JAK2 and STAT3 decreased. After treatment with scutellarin, PC12 cells apoptosis as well as cleaved caspase-3 and Bax protein expression and fluorescence intensity decreased. The expression and fluorescence intensity of Bcl-2, phosphorylated JAK2, and STAT3 increased. AG490, a specific inhibitor of the JAK2/STAT3 signalling pathway, was used. Our findings suggest that AG490 attenuates the effects of scutellarin. Our study revealed that scutellarin inhibited OGD-activated microglia-mediated PC12 cells apoptosis which was regulated via the JAK2/STAT3 signalling pathway.
Collapse
Affiliation(s)
- Zhao-Da Duan
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Li-Yang Zheng
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Qiu-Ye Jia
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Hao-Lun Chen
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Dong-Yao Xu
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Yu-Jia Yang
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Zhi Qi
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China
| | - Li Yang
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China.
| | - Chun-Yun Wu
- Department of Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, China.
| |
Collapse
|
|
19
|
Li K, Li H, He A, Zhang G, Jin Y, Cai J, Ye C, Qi L, Liu Y. Deciphering the role of transcription factors in glioblastoma cancer stem cells. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1245-1255. [PMID: 38716541 PMCID: PMC11543521 DOI: 10.3724/abbs.2024061] [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: 12/13/2023] [Accepted: 03/07/2024] [Indexed: 10/17/2024] Open
Abstract
Glioblastoma (GBM), the most aggressive and fatal brain malignancy, is largely driven by a subset of tumor cells known as cancer stem cells (CSCs). CSCs possess stem cell-like properties, including self-renewal, proliferation, and differentiation, making them pivotal for tumor initiation, invasion, metastasis, and overall tumor progression. The regulation of CSCs is primarily controlled by transcription factors (TFs) which regulate the expressions of genes involved in maintaining stemness and directing differentiation. This review aims to provide a comprehensive overview of the role of TFs in regulating CSCs in GBM. The discussion encompasses the definitions of CSCs and TFs, the significance of glioma stem cells (GSCs) in GBM, and how TFs regulate GSC self-renewal, proliferation, differentiation, and transformation. The potential for developing TF-targeted GSC therapies is also explored, along with future research directions. By understanding the regulation of GSCs by TFs, we may uncover novel diagnostic and therapeutic strategies against this devastating disease of GBM.
Collapse
Affiliation(s)
- Kaishu Li
- Department of Neurosurgery & Medical Research
CenterShunde HospitalSouthern Medical University (The First People’s
Hospital of Shunde Foshan)Foshan528300China
- Department of NeurosurgeryNanfang HospitalSouthern Medical UniversityGuangzhou510515China
| | - Haichao Li
- Institute of Digestive DiseaseAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Aonan He
- Department of NeurosurgeryAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Gengqiang Zhang
- Department of NeurosurgeryAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Yuyao Jin
- Department of NeurosurgeryAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Junbin Cai
- Department of NeurosurgeryAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Chenle Ye
- Department of NeurosurgeryAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Ling Qi
- Institute of Digestive DiseaseAffiliated Qingyuan HospitalGuangzhou Medical UniversityQingyuan People’s HospitalQingyuan511518China
| | - Yawei Liu
- Department of Neurosurgery & Medical Research
CenterShunde HospitalSouthern Medical University (The First People’s
Hospital of Shunde Foshan)Foshan528300China
| |
Collapse
|
|
20
|
Lee B, Park Y, Lee Y, Kwon S, Shim J. Triptolide, a Cancer Cell Proliferation Inhibitor, Causes Zebrafish Muscle Defects by Regulating Notch and STAT3 Signaling Pathways. Int J Mol Sci 2024; 25:4675. [PMID: 38731894 PMCID: PMC11083231 DOI: 10.3390/ijms25094675] [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: 03/07/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes within the cell, including Notch1 and STAT3 signaling. Our research showed that triptolide reduces cancer cell proliferation by decreasing the expression of downstream targets of these signals. The levels of each signal-related protein and mRNA were analyzed using Western blot and qPCR methods. Interestingly, inhibiting one signal with a single inhibitor alone did not significantly reduce cancer cell proliferation. Instead, MTT assays showed that the simultaneous inhibition of Notch1 and STAT3 signaling reduced cell proliferation. The effect of triptolide was similar to a combination treatment with inhibitors for both signals. When we conducted a study on the impact of triptolide on zebrafish larvae, we found that it inhibited muscle development and interfered with muscle cell proliferation, as evidenced by differences in the staining of myosin heavy chain and F-actin proteins in confocal fluorescence microscopy. Additionally, we noticed that inhibiting a single type of signaling did not lead to any significant muscle defects. This implies that triptolide obstructs multiple signals simultaneously, including Notch1 and STAT3, during muscle development. Chemotherapy is commonly used to treat cancer, but it may cause muscle loss due to drug-related adverse reactions or other complex mechanisms. Our study suggests that anticancer agents like triptolide, inhibiting essential signaling pathways including Notch1 and STAT3 signaling, may cause muscle atrophy through anti-proliferative activity.
Collapse
Affiliation(s)
- Byongsun Lee
- Department of Bioresources Engineering, Sejong University, Seoul 05006, Republic of Korea; (B.L.); (Y.P.); (Y.L.); (S.K.)
- Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Yongjin Park
- Department of Bioresources Engineering, Sejong University, Seoul 05006, Republic of Korea; (B.L.); (Y.P.); (Y.L.); (S.K.)
| | - Younggwang Lee
- Department of Bioresources Engineering, Sejong University, Seoul 05006, Republic of Korea; (B.L.); (Y.P.); (Y.L.); (S.K.)
| | - Seyoung Kwon
- Department of Bioresources Engineering, Sejong University, Seoul 05006, Republic of Korea; (B.L.); (Y.P.); (Y.L.); (S.K.)
| | - Jaekyung Shim
- Department of Bioresources Engineering, Sejong University, Seoul 05006, Republic of Korea; (B.L.); (Y.P.); (Y.L.); (S.K.)
| |
Collapse
|
|
21
|
Akter R, Park R, Lee SK, Han EJ, Park KS, Park J, Cho MY. Upregulation of EMR1 (ADGRE1) by Tumor-Associated Macrophages Promotes Colon Cancer Progression by Activating the JAK2/STAT1,3 Signaling Pathway in Tumor Cells. Int J Mol Sci 2024; 25:4388. [PMID: 38673975 PMCID: PMC11050366 DOI: 10.3390/ijms25084388] [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: 02/18/2024] [Revised: 04/12/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Previously, we reported that epidermal growth factor-like module-containing mucin-like hormone receptor-like 1 (EMR1/ADGRE1) is abnormally expressed in colon cancer (CC) and is a risk factor for lymph node metastasis (LNM) and poor recurrence-free survival in patients with abundant tumor-associated macrophages (TAMs). However, the signaling pathways associated with EMR1 expression in CC progression remain unclear. In this study, we aimed to explore the role of EMR1 and its signaling interactions with macrophages in CC progression. Spatial transcriptomics of pT3 microsatellite unstable CC tissues revealed heightened Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in EMR1-HL CC with LNM compared to EMR1-N CC without LNM. Through in vitro coculture of CC cells with macrophages, EMR1 expression by CC cells was found to be induced by TAMs, ultimately interacting with upregulated JAK/STAT signaling, increasing cell proliferation, migration, and motility, and reducing apoptosis. JAK2/STAT3 inhibition decreased the levels of EMR1, JAK2, STAT1, and STAT3, significantly impeded the proliferation, migration, and mobility of cells, and increased the apoptosis of EMR1+ CC cells compared to their EMR1KO counterparts. Overall, TAMs-induced EMR1 upregulation in CC cells may promote LNM and CC progression via JAK2/STAT1,3 signaling upregulation. This study provides further insights into the molecular mechanisms involving macrophages and intracellular EMR1 expression in CC progression, suggesting its clinical significance and offering potential interventions to enhance patient outcomes.
Collapse
Affiliation(s)
- Rokeya Akter
- Department of Global Medical Science, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Rackhyun Park
- Department of Life Science, Yong-In University, Yongin 17092, Republic of Korea;
| | - Soo Kyung Lee
- Department of Physiology, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea; (S.K.L.); (K.-S.P.)
| | - Eun ju Han
- Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea; (S.K.L.); (K.-S.P.)
| | - Junsoo Park
- Division of Biological Science and Technology, Yonsei University, Wonju 26426, Republic of Korea;
| | - Mee-Yon Cho
- Department of Global Medical Science, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea;
- Department of Pathology, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea;
| |
Collapse
|
|
22
|
Mohamed Allam D, Kasem H, Hegazy A, Mahmoud SF. Role of CTLA4 and pSTAT3 Immunostaining in Prognosis and Treatment of the Colorectal Carcinoma. IRANIAN JOURNAL OF PATHOLOGY 2024; 19:89-102. [PMID: 38864078 PMCID: PMC11164302 DOI: 10.30699/ijp.2024.2009619.3158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/07/2023] [Indexed: 06/13/2024]
Abstract
Background & Objective Colorectal carcinoma (CRC) is the third leading cause of cancer-caused death worldwide and constitutes about 6.48% of all malignancies in Egypt. Studying the molecular profile of CRC is essential for developing targeted therapies. STAT3 and CTLA4 expression are considered as molecular abnormalities involved in the CRC progression and chemo-resistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate pSTAT3 and CTLA4 expression levels and their possible roles as prognostic and predictive biomarkers in CRC using immunohistochemistry (IHC). Methods This retrospective study included 113 CRC patients. Tissue microarrays were constructed, followed by pSTAT3 and CTLA4 antibodies immunostaining. Their expression was assessed and compared with the clinicopathological parameters and survival data. Results Both pSTAT3 and CTLA4 overexpression were significantly associated with poor prognostic parameters, such as the presence of distant metastasis (P=0.02 & 0.03), high grade (P<0.001 & 0.03), high mitotic count (P<0.001 & 0.03), high tumor budding group (P=0.008 & 0.04), infiltrating tumor border (P<0.001 & 0.007) respectively, and advanced pathological stage with pSTAT3 (P=0.02). A significant association was found between overexpression of both markers and short overall survival. Correlations between the H-score of pSTAT3 and CTLA4 in CRC showed a significant positive correlation (P<0.001). Conclusion STAT3 and CTLA4 positivity may be linked to the development and progression of the CRC, and they may provide potential prognostic indicators and therapeutic targets for CRC patients.
Collapse
Affiliation(s)
- Dina Mohamed Allam
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Hend Kasem
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Amira Hegazy
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Menoufia University, Egypt
| | - Shereen F Mahmoud
- Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| |
Collapse
|
|
23
|
Hiura K, Watanabe M, Hirose N, Nakano K, Okamura T, Sasaki H, Sasaki N. Mitotic Spindle Positioning (MISP) Facilitates Colorectal Cancer Progression by Forming a Complex with Opa Interacting Protein 5 (OIP5) and Activating the JAK2-STAT3 Signaling Pathway. Int J Mol Sci 2024; 25:3061. [PMID: 38474305 DOI: 10.3390/ijms25053061] [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: 12/26/2023] [Revised: 02/09/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
Patients with inflammatory bowel disease (IBD) who experience long-term chronic inflammation of the colon are at an increased risk of developing colorectal cancer (CRC). Mitotic spindle positioning (MISP), an actin-binding protein, plays a role in mitosis and spindle positioning. MISP is found on the apical membrane of the intestinal mucosa and helps stabilize and elongate microvilli, offering protection against colitis. This study explored the role of MISP in colorectal tumorigenesis using a database, human CRC cells, and a mouse model for colitis-induced colorectal tumors triggered by azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment. We found that MISP was highly expressed in colon cancer patient tissues and that reduced MISP expression inhibited cell proliferation. Notably, MISP-deficient mice showed reduced colon tumor formation in the AOM/DSS-induced colitis model. Furthermore, MISP was found to form a complex with Opa interacting protein 5 (OIP5) in the cytoplasm, influencing the expression of OIP5 in a unidirectional manner. We also observed that MISP increased the levels of phosphorylated STAT3 in the JAK2-STAT3 signaling pathway, which is linked to tumorigenesis. These findings indicate that MISP could be a risk factor for CRC, and targeting MISP might provide insights into the mechanisms of colitis-induced colorectal tumorigenesis.
Collapse
Affiliation(s)
- Koki Hiura
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Japan
| | - Masaki Watanabe
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Japan
| | - Naoki Hirose
- The Institute of Experimental Animal Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Kenta Nakano
- Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Tadashi Okamura
- Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Hayato Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Japan
| | - Nobuya Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Towada 034-8628, Japan
| |
Collapse
|
|
24
|
Yang Y, Wu J, Feng S, Yu H, Liu C, Wang S. Notoginsenoside R1 attenuates bupivacaine induced neurotoxicity by activating Jak1/Stat3/Mcl1 pathway. Toxicology 2024; 503:153740. [PMID: 38316350 DOI: 10.1016/j.tox.2024.153740] [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: 12/26/2023] [Revised: 01/29/2024] [Accepted: 02/01/2024] [Indexed: 02/07/2024]
Abstract
Bupivacaine, a common amide local anesthetic, can provide effective analgesia or pain relief but can also cause neurotoxicity, which remains a mounting concern in clinic and animal care. However, the precise underlying mechanisms have not been fully elucidated. A natural compound, notoginsenoside R1 (NG-R1) has been reported to exhibit a neuroprotective role in stress conditions. In this study, we explored the function and mechanism of NG-R1 in alleviating bupivacaine-induced neurotoxicity in mouse hippocampal neuronal (HT-22) and mouse neuroblastoma (Neuro-2a) cell lines. Our results exhibited that NG-R1 treatment can significantly rescue the decline of cell survival induced by bupivacaine. Tunel staining and western blotting showed that NG-R1 could attenuate BPV‑induced cell apoptosis. Besides, we focused on Mcl1 as a potential target as it showed opposite expression tendency in response to NG-R1 and bupivacaine exposure. Mcl1 knockdown blocked the inhibitory effect of NG-R1 on cell apoptosis against bupivacaine treatment. Intriguingly, we found that NG-R1 can upregulate Mcl1 transcription by activating Stat3 and promote its nuclear translocation. In addition, NG-R1 can also promote Jak1 phosphorylation and docking analysis provide a predicted model for interaction between NG-R1 and phosphorylated Jak1. Taken together, our results demonstrated that NG-R1 can attenuate bupivacaine induced neurotoxicity by activating Jak1/Stat3/Mcl1 pathway.
Collapse
Affiliation(s)
- Yu Yang
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China
| | - Jiwen Wu
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China
| | - Shicheng Feng
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China
| | - Hao Yu
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China
| | - Chuanxin Liu
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China; Department of Psychiatry, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
| | - Shuai Wang
- School of Mental Health, Jining Medical University, Jining 272013, China; Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Jining Medical University, Jining, Shandong, China.
| |
Collapse
|
|
25
|
Prajapati KS, Kumar S. Kurarinone targets JAK2-STAT3 signaling in colon cancer-stem-like cells. Cell Biochem Funct 2024; 42:e3959. [PMID: 38390770 DOI: 10.1002/cbf.3959] [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: 10/24/2023] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
Natural compounds are known to regulate stemness/self-renewal properties in colon cancer cells at molecular level. In the present study, we first time studied the colon cancer stem-like cells targeting potential of Kurarinone (KU) and explored the underlying mechanism. Cytotoxic potential of KU was checked in colon cancer cells. Colonosphere formation assay was performed to check the spheroid formation reduction potential of KU in HCT-116 cells by using phase-contrast microscopy. Stemness/self-renewal marker expression was studied at mRNA and protein levels in colonosphere. The qRT-PCR, western blot analysis, and flow cytometer techniques were used to assess the effect of KU treatment on cell cycle progression and apoptosis induction in colon cancer cells and colonosphere. Further, effect of KU treatment on pSTAT3 status and its nuclear translocation was also studied. KU treatment significantly decreased HCT-116 cell proliferation and reduced sphere formation potential at IC30 (8.71 µM) and IC50 (20.34 µM) concentrations compared to respective vehicle-treated groups, respectively. KU exposure significantly reduced the expression of CD44, c-Myc, Bmi-1, and Sox2 stemness/self-renewal markers in colonosphere in a dose-dependent manner. KU treatment inhibits JAK2-STAT3 signaling pathway by reducing pSTAT3 levels and its nuclear translocation in HCT-116 cells and colonosphere at IC50 concentration. KU treatment significantly decreased the expression of CCND1 and CDK4 cell cycle-specific markers and arrested the HCT-116 cells and colonosphere in G1-phase. Further, KU treatment increased Bax/Bcl-2 ratio, apoptotic cell population, cleaved caspase 3, and PARP-1 in HCT-116 cells and colonosphere. In conclusion, KU treatment decreases stemness/self-renewal, induces cell cycle arrest and apoptosis in HCT-116 colonosphere by down-regulating CD44-JAK2-STAT3 axis. Thus, targeting stemness/self-renewal and other cancer hallmark(s) by KU through CD44/JAK2/STAT3 signaling pathway might be a novel strategy to target colon cancer stem-like cells.
Collapse
Affiliation(s)
- Kumari Sunita Prajapati
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | - Shashank Kumar
- Molecular Signaling & Drug Discovery Laboratory, Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| |
Collapse
|
|
26
|
Lee J, Heo SC, Kim Y. Combination of oxaliplatin and β-carotene suppresses colorectal cancer by regulating cell cycle, apoptosis, and cancer stemness in vitro. Nutr Res Pract 2024; 18:62-77. [PMID: 38352212 PMCID: PMC10861335 DOI: 10.4162/nrp.2024.18.1.62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/12/2023] [Accepted: 12/06/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES Colorectal cancer (CRC) is the third most common cancer worldwide with a high recurrence rate. Oxaliplatin (OXA) resistance is one of the major reasons hindering CRC therapy. β-Carotene (BC) is a provitamin A and is known to have antioxidant and anticancer effects. However, the combined effect of OXA and BC has not been investigated. Therefore, this study investigated the anticancer effects and mechanism of the combination of OXA and BC on CRC. MATERIALS/METHODS In the present study, the effects of the combination of OXA and BC on cell viability, cell cycle arrest, and cancer stemness were investigated using HCT116, HT29, OXA-resistant cells, and human CRC organoids. RESULTS The combination of OXA and BC enhanced apoptosis, G2/M phase cell cycle arrest, and inhibited cancer cell survival in human CRC resistant cells and CRC organoids without toxicity in normal organoids. Cancer stem cell marker expression and self-replicating capacity were suppressed by combined treatment with OXA and BC. Moreover, this combined treatment upregulated apoptosis and the stem cell-related JAK/STAT signaling pathway. CONCLUSIONS Our results suggest a novel potential role of BC in reducing resistance to OXA, thereby enhances the anticancer effects of OXA. This enhancement is achieved through the regulation of cell cycle, apoptosis, and stemness in CRC.
Collapse
Affiliation(s)
- Junghyeun Lee
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea
| | - Seung Chul Heo
- Department of Surgery, Seoul National University-Seoul Metropolitan Government (SNU-SMG) Boramae Medical Center, Seoul 07061, Korea
| | - Yuri Kim
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea
- Graduate Program in System Health Science and Engineering, Ewha Womans University, Seoul 03760, Korea
| |
Collapse
|
|
27
|
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.
Collapse
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
| |
Collapse
|
|
28
|
Choi JW, Kim SW, Kim HS, Kang MJ, Kim SA, Han JY, Kim H, Ku SY. Effects of Melatonin, GM-CSF, IGF-1, and LIF in Culture Media on Embryonic Development: Potential Benefits of Individualization. Int J Mol Sci 2024; 25:751. [PMID: 38255823 PMCID: PMC10815572 DOI: 10.3390/ijms25020751] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
The implantation of good-quality embryos to the receptive endometrium is essential for successful live birth through in vitro fertilization (IVF). The higher the quality of embryos, the higher the live birth rate per cycle, and so efforts have been made to obtain as many high-quality embryos as possible after fertilization. In addition to an effective controlled ovarian stimulation process to obtain high-quality embryos, the composition of the embryo culture medium in direct contact with embryos in vitro is also important. During embryonic development, under the control of female sex hormones, the fallopian tubes and endometrium create a microenvironment that supplies the nutrients and substances necessary for embryos at each stage. During this process, the development of the embryo is finely regulated by signaling molecules, such as growth factors and cytokines secreted from the epithelial cells of the fallopian tube and uterine endometrium. The development of embryo culture media has continued since the first successful human birth through IVF in 1978. However, there are still limitations to mimicking a microenvironment similar to the reproductive organs of women suitable for embryo development in vitro. Efforts have been made to overcome the harsh in vitro culture environment and obtain high-quality embryos by adding various supplements, such as antioxidants and growth factors, to the embryo culture medium. Recently, there has been an increase in the number of studies on the effect of supplementation in different clinical situations such as old age, recurrent implantation failure (RIF), and unexplained infertility; in addition, anticipation of the potential benefits from individuation is rising. This article reviews the effects of representative supplements in culture media on embryo development.
Collapse
Affiliation(s)
- Jung-Won Choi
- Laboratory of In Vitro Fertilization, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (J.-W.C.); (H.-S.K.); (M.-J.K.); (S.-A.K.)
| | - Sung-Woo Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (S.-W.K.); (J.-Y.H.); (H.K.)
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hee-Sun Kim
- Laboratory of In Vitro Fertilization, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (J.-W.C.); (H.-S.K.); (M.-J.K.); (S.-A.K.)
| | - Moon-Joo Kang
- Laboratory of In Vitro Fertilization, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (J.-W.C.); (H.-S.K.); (M.-J.K.); (S.-A.K.)
| | - Sung-Ah Kim
- Laboratory of In Vitro Fertilization, Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (J.-W.C.); (H.-S.K.); (M.-J.K.); (S.-A.K.)
| | - Ji-Yeon Han
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (S.-W.K.); (J.-Y.H.); (H.K.)
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hoon Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (S.-W.K.); (J.-Y.H.); (H.K.)
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Seung-Yup Ku
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Republic of Korea; (S.-W.K.); (J.-Y.H.); (H.K.)
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
| |
Collapse
|
|
29
|
Bani N, Rahmani F, Shakour N, Amerizadeh F, Khalili-Tanha G, Khazaei M, Hassanian SM, Kerachian MA, Abbaszadegan MR, Mojarad M, Hadizadeh F, Ferns GA, Avan A. Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway. Anticancer Agents Med Chem 2024; 24:916-927. [PMID: 38584531 DOI: 10.2174/0118715206296355240325113920] [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: 01/08/2024] [Revised: 03/02/2024] [Accepted: 03/13/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC. METHODS Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively. RESULTS Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels. CONCLUSION This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.
Collapse
Affiliation(s)
- Nastaran Bani
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Forouzan Amerizadeh
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mojarad
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzin Hadizadeh
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Department of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
30
|
Rajabi S, Irani M, Moeinifard M, Hamzeloo-Moghadam M. Britannin suppresses MCF-7 breast cancer cell growth by inducing apoptosis and inhibiting autophagy. AVICENNA JOURNAL OF PHYTOMEDICINE 2024; 14:90-99. [PMID: 38948174 PMCID: PMC11210692 DOI: 10.22038/ajp.2023.22995] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 07/02/2024]
Abstract
Objective Breast cancer is the main reason for cancer-related death in women. Britannin is a sesquiterpene lactone compound derived from Inula aucheriana with anti-tumor properties. We aimed to explore the impacts of britannin on apoptosis and autophagy in MCF-7 breast cancer cell line. Materials and Methods The cytotoxic influences of britannin on MCF-7 cells were estimated by the MTT method. The expression levels of apoptosis-associated genes such as CASP3, BCL2, BCL2L1, STAT3, and JAK2 and transcripts of autophagy markers including ATG1, ATG4, ATG5, ATG7, ATG12, BECN1, and MAP1LC3A were quantified using quantitative real time-PCR (qRT-PCR). Western blotting method was used to evaluate the amount of caspase 3, phosphorylated JAK2, phosphorylated STAT3, ATG1, ATG4, ATG5, Beclin1, and LC-III. Results Treatment of MCF-7 cells with various concentrations of britannin remarkably hindered the viability of these cells compared to the controls. This compound significantly elevated the expression of pro-apoptotic caspase-3 but did not influence the levels of anti-apoptotic BCL2 and BCL2L1. Britannin decreased the levels of phosphorylated forms of JAK2 and STAT3 proteins causing the blockage of the JAK/STAT pathway. Four autophagy factors expressions, including ATG4, ATG5, Beclin1, and LCIII, were reduced due to the effect of britannin on MCF-7 cells. Conclusion Britannin triggered apoptosis in MCF-7 cells by a mechanism that led to the blockade of the JAK/STAT pathway. Moreover, britannin prohibited autophagy in these cancer cells. This may suggest britannin as an agent for the suppression of breast tumors or as an adjutant for the enhancement of anti-breast cancer drugs effect.
Collapse
Affiliation(s)
- Sadegh Rajabi
- Traditional Medicine and Materia Medica Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Irani
- Traditional Medicine and Materia Medica Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Moeinifard
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Hamzeloo-Moghadam
- Traditional Medicine and Materia Medica Research Center and Department of Traditional Pharmacy, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
31
|
Molenda S, Sikorska A, Florczak A, Lorenc P, Dams-Kozlowska H. Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer-Drug Carriers Matter. Cancers (Basel) 2023; 15:5647. [PMID: 38067351 PMCID: PMC10705165 DOI: 10.3390/cancers15235647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 09/08/2024] Open
Abstract
High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.
Collapse
Affiliation(s)
- Sara Molenda
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Agata Sikorska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Anna Florczak
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Patryk Lorenc
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| |
Collapse
|
|
32
|
Guo M, Shen D, Su Y, Xu J, Zhao S, Zhang W, Wang Y, Jiang W, Wang J, Geng X, Ding X, Xu X. Syndecan-1 shedding destroys epithelial adherens junctions through STAT3 after renal ischemia/reperfusion injury. iScience 2023; 26:108211. [PMID: 37942007 PMCID: PMC10628745 DOI: 10.1016/j.isci.2023.108211] [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: 04/05/2023] [Revised: 07/22/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Adherens junctions between tubular epithelial cells are disrupted in renal ischemia/reperfusion (I/R) injury. Syndecan-1 (SDC-1) is involved in maintaining cell morphology. We aimed to study the role of SDC-1 shedding induced by renal I/R in the destruction of intracellular adherens junctions. We found that SDC-1 shedding was increased while the expression of E-cadherin was decreased. This observation was accompanied by the activation of STAT3 in the kidneys. Inhibiting the shedding of SDC-1 induced by I/R could alleviate this effect. Mild renal I/R could induce more severe renal injury, lower E-cadherin expression, damaged cell junctions, and activated STAT3 in knockout mice with the tubule-specific deletion of SDC-1 mice. The results in vitro were consistent with those in vivo. Inhibiting the shedding of SDC-1 could alleviate the decreased expression of E-cadherin and damage of cell adherens junctions through inhibiting the activation of STAT3 during ischemic acute kidney injury.
Collapse
Affiliation(s)
- Man Guo
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Daoqi Shen
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Yiqi Su
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Jiarui Xu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Shuan Zhao
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Weidong Zhang
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Yaqiong Wang
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Wuhua Jiang
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Jialin Wang
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Xuemei Geng
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Xiaoqiang Ding
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| | - Xialian Xu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Medical Center of Kidney Disease, Shanghai, China
- Shanghai Institute of Kidney and Dialysis, Shanghai, China
- Key Laboratory of Kidney and Blood Purification, Shanghai, China
- Hemodialysis quality control center of Shanghai, Shanghai, China
| |
Collapse
|
|
33
|
Abdelhafez OH, Abdel-Rahman IM, Alaaeldin E, Refaat H, El-Sayed R, Al-Harbi SA, Shawky AM, Hegazy MEF, Moustafa AY, Shady NH. Pro-Apoptotic Activity of Epi-Obtusane against Cervical Cancer: Nano Formulation, In Silico Molecular Docking, and Pharmacological Network Analysis. Pharmaceuticals (Basel) 2023; 16:1578. [PMID: 38004443 PMCID: PMC10674245 DOI: 10.3390/ph16111578] [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: 08/29/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer is a major disease that threatens human health all over the world. Intervention and prevention in premalignant processes are successful ways to prevent cancer from striking. On the other hand, the marine ecosystem is a treasure storehouse of promising bioactive metabolites. The use of such marine products can be optimized by selecting a suitable nanocarrier. Therefore, epi-obtusane, previously isolated from Aplysia oculifera, was investigated for its potential anticancer effects toward cervical cancer through a series of in vitro assays in HeLa cells using the MTT assay method. Additionally, the sesquiterpene was encapsulated within a liposomal formulation (size = 130.8 ± 50.3, PDI = 0.462, zeta potential -12.3 ± 2.3), and the antiproliferative potential of epi-obtusane was investigated against the human cervical cancer cell line HeLa before and after encapsulation with liposomes. Epi-obtusane exhibited a potent effect against the HeLa cell line, while the formulated molecule with liposomes increased the in vitro antiproliferative activity. Additionally, cell cycle arrest analysis, as well as the apoptosis assay, performed via FITC-Annexin-V/propidium iodide double staining (flow cytofluorimetry), were carried out. The pharmacological network enabled us to deliver further insights into the mechanism of epi-obtusane, suggesting that STAT3 might be targeted by the compound. Moreover, molecular docking showed a comparable binding score of the isolated compound towards the STAT3 SH2 domain. The targets possess an anticancer effect through the endometrial cancer pathway, regulation of DNA templated transcription, and nitric oxide synthase, as mentioned by the KEGG and ShinyGo 7.1 databases.
Collapse
Affiliation(s)
- Omnia Hesham Abdelhafez
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia 61111, Egypt
| | - Islam M. Abdel-Rahman
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New-Minia 61111, Egypt;
| | - Eman Alaaeldin
- Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
- Department of Pharmaceutics, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia 61111, Egypt
| | - Hesham Refaat
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52246, USA;
| | - Refat El-Sayed
- Department of Chemistry, University College in Al-Jamoum, Umm Al-Qura University, Makkah 24231, Saudi Arabia; (R.E.-S.); (S.A.A.-H.)
- Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt
| | - Sami A. Al-Harbi
- Department of Chemistry, University College in Al-Jamoum, Umm Al-Qura University, Makkah 24231, Saudi Arabia; (R.E.-S.); (S.A.A.-H.)
| | - Ahmed M. Shawky
- Science and Technology Unit (STU), Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Mohamed-Elamir F. Hegazy
- Chemistry of Medicinal Plants Department, National Research Centre, El-Tahrir Street, Dokki, Giza 12622, Egypt;
| | - Alaa Y. Moustafa
- Zoology Department, Faculty of Science, Sohag University, Sohag 82524, Egypt;
| | - Nourhan Hisham Shady
- Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia 61111, Egypt
| |
Collapse
|
|
34
|
Hashemi M, Abbaszadeh S, Rashidi M, Amini N, Talebi Anaraki K, Motahhary M, Khalilipouya E, Harif Nashtifani A, Shafiei S, Ramezani Farani M, Nabavi N, Salimimoghadam S, Aref AR, Raesi R, Taheriazam A, Entezari M, Zha W. STAT3 as a newly emerging target in colorectal cancer therapy: Tumorigenesis, therapy response, and pharmacological/nanoplatform strategies. ENVIRONMENTAL RESEARCH 2023; 233:116458. [PMID: 37348629 DOI: 10.1016/j.envres.2023.116458] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/11/2023] [Accepted: 06/17/2023] [Indexed: 06/24/2023]
Abstract
Colorectal cancer (CRC) ranks as the third most aggressive tumor globally, and it can be categorized into two forms: colitis-mediated CRC and sporadic CRC. The therapeutic approaches for CRC encompass surgical intervention, chemotherapy, and radiotherapy. However, even with the implementation of these techniques, the 5-year survival rate for metastatic CRC remains at a mere 12-14%. In the realm of CRC treatment, gene therapy has emerged as a novel therapeutic approach. Among the crucial molecular pathways that govern tumorigenesis, STAT3 plays a significant role. This pathway is subject to regulation by cytokines and growth factors. Once translocated into the nucleus, STAT3 influences the expression levels of factors associated with cell proliferation and metastasis. Literature suggests that the upregulation of STAT3 expression is observed as CRC cells progress towards metastatic stages. Consequently, elevated STAT3 levels serve as a significant determinant of poor prognosis and can be utilized as a diagnostic factor for cancer patients. The biological and malignant characteristics of CRC cells contribute to low survival rates in patients, as the upregulation of STAT3 prevents apoptosis and promotes pro-survival autophagy, thereby accelerating tumorigenesis. Furthermore, STAT3 plays a role in facilitating the proliferation of CRC cells through the stimulation of glycolysis and promoting metastasis via the induction of epithelial-mesenchymal transition (EMT). Notably, an intriguing observation is that the upregulation of STAT3 can mediate resistance to 5-fluorouracil, oxaliplatin, and other anti-cancer drugs. Moreover, the radio-sensitivity of CRC diminishes with increased STAT3 expression. Compounds such as curcumin, epigallocatechin gallate, and other anti-tumor agents exhibit the ability to suppress STAT3 and its associated pathways, thereby impeding tumorigenesis in CRC. Furthermore, it is worth noting that nanostructures have demonstrated anti-proliferative and anti-metastatic properties in CRC.
Collapse
Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sahar Abbaszadeh
- Faculty of Medicine, Islamic Azad University Tonekabon Branch, Tonekabon, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nafisesadat Amini
- Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | | | - Ensi Khalilipouya
- Department of Radiology, Mahdiyeh Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Sasan Shafiei
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA
| | - Rasoul Raesi
- Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, 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; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Wenliang Zha
- Second Affiliated Hospital, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
| |
Collapse
|
|
35
|
Hsieh YC, Dai YC, Cheng KT, Yang WT, Ramani MV, Subbaraju GV, Chen YJ, Chang CC. Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether. Biomedicines 2023; 11:2530. [PMID: 37760971 PMCID: PMC10526010 DOI: 10.3390/biomedicines11092530] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/03/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/β-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.
Collapse
Affiliation(s)
- Ya-Chu Hsieh
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung 402202, Taiwan;
| | - Yuan-Chang Dai
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan;
- Department of Laboratory Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung 402202, Taiwan
| | - Kur-Ta Cheng
- Department of Biochemistry and Molecular Cell Biology, Taipei Medical University, Taipei 110301, Taiwan;
| | - Wei-Ting Yang
- Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan;
| | - Modukuri V. Ramani
- Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India; (M.V.R.); (G.V.S.)
| | | | - Yi-Ju Chen
- Department of Dermatology, Taichung Veterans General Hospital, Taichung 407219, Taiwan
- Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung 402202, Taiwan
| | - Chia-Che Chang
- Doctoral Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung 402202, Taiwan;
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung 402202, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung 402202, Taiwan;
- Graduate Institute of Biomedical Sciences, Doctoral Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung 402202, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413305, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 404333, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110301, Taiwan
| |
Collapse
|
|
36
|
Jahangiri A, Ezzeddini R, Zounemat Kermani N, Bahrami F, Salek Farrokhi A. Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti-breast cancer immunity: An in vitro study. Scand J Immunol 2023; 98:e13300. [PMID: 38441231 DOI: 10.1111/sji.13300] [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: 12/17/2022] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 03/07/2024]
Abstract
Breast cancer (BC) is the most prevalent diagnosed cancer among women. Herceptin blocks the effects of Her-2 and tumour cell growth. Despite many achievements using Herceptin in Her-2+ invasive BC treatment, there are treatment failures and resistances. The signal transducer and activator of transcription 3 (STAT3) is persistently activated in BC and is associated with immune suppression and tumour cell proliferation. We evaluated whether STAT3 inhibition could increase Herceptin impact on in vitro reduction of immune checkpoint inhibitors and polarize T cells to a protective immune response. We treated SK-BR-3 cells with Herceptin and the STAT3-inhibitor (FLLL32) and assessed the apoptosis and expression of apoptosis-related proteins, VEGF, Her-2 and apoptosis targets of STAT3. PBMCs were isolated from healthy donors and co-cultured with SK-BR-3 cells in the presence or absence of Herceptin and FLLL32. PD-L1, CTLA-4, TIM-3 and T-cell intracellular cytokines were then evaluated. Our results demonstrated that STAT3 inhibition and Herceptin increased SK-BR-3 cell apoptosis, significantly. STAT3 inhibition through combination treatment had a more significant effect on regulating PD-1, TIM-3 and CTLA-4 expression on PBMCs. Alternatively, the combination of FLLL32 and Herceptin promoted T helper-1 protective immune response. The combination of FLLL32 and Herceptin suppress the expression of immune checkpoints and provoke the T-helper1 immune response in lymphocytes. Our analysis indicates STAT3 as a promising target that improves Herceptin's role in breast cancer cell apoptosis.
Collapse
Affiliation(s)
- Amirhossein Jahangiri
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rana Ezzeddini
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Fariborz Bahrami
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | | |
Collapse
|
|
37
|
Lange F, Porath K, Sellmann T, Einsle A, Jaster R, Linnebacher M, Köhling R, Kirschstein T. Direct-Current Electrical Field Stimulation of Patient-Derived Colorectal Cancer Cells. BIOLOGY 2023; 12:1032. [PMID: 37508461 PMCID: PMC10376471 DOI: 10.3390/biology12071032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/17/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
Several cues for a directional migration of colorectal cancer cells were identified as being crucial in tumor progression. However, galvanotaxis, the directional migration in direct-current electrical fields, has not been investigated so far. Therefore, we asked whether direct-current electrical fields could be used to mobilize colorectal cancer cells along field vectors. For this purpose, five patient-derived low-passage cell lines were exposed to field strengths of 150-250 V/m in vitro, and migration along the field vectors was investigated. To further study the role of voltage-gated calcium channels on galvanotaxis and intracellular signaling pathways that are associated with migration of colorectal cancer cells, the cultures were exposed to selective inhibitors. In three out of five colorectal cancer cell lines, we found a preferred cathodal migration. The cellular integrity of the cells was not impaired by exposure of the cells to the selected field strengths. Galvanotaxis was sensitive to inhibition of voltage-gated calcium channels. Furthermore, signaling pathways such as AKT and MEK, but not STAT3, were also found to contribute to galvanotaxis in our in vitro model system. Overall, we identify electrical fields as an important contributor to the directional migration of colorectal cancer cells.
Collapse
Affiliation(s)
- Falko Lange
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Katrin Porath
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Tina Sellmann
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Anne Einsle
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Robert Jaster
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Rüdiger Köhling
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Timo Kirschstein
- Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, 18057 Rostock, Germany
| |
Collapse
|
|
38
|
Li YJ, Tang DX, Yan HT, Yang B, Yang Z, Long FX. Network pharmacology and molecular docking-based analyses to predict the potential mechanism of Huangqin decoction in treating colorectal cancer. World J Clin Cases 2023; 11:4553-4566. [PMID: 37469733 PMCID: PMC10353508 DOI: 10.12998/wjcc.v11.i19.4553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/27/2023] [Accepted: 06/13/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND To analyze the potential action mechanism of Huangqin decoction (HQD) in colorectal cancer (CRC) treatment on the basis of network pharmacology and molecular docking.
AIM To investigate the molecular mechanisms of HQD for CRC treatment by using network pharmacology and molecular docking.
METHODS All HQD active ingredients were searched using the Systematic Pharmacology and Traditional Chinese Medicine Systems Pharmacology databases and the Bioinformatics Analysis Tool for Molecular Mechanisms in traditional Chinese medicine. Then, the targets of the active ingredients were screened. The abbreviations of protein targets were obtained from the UniProt database. A “drug–compound–target” network was constructed to screen for some main active ingredients. Some targets related to the therapeutic effect of CRC were obtained from the GeneCards, DisGeNET, Therapeutic Target Database, and Online Mendelian Inheritance in Man databases. The intersection of targets of Chinese herbs and CRC was taken. A Venn diagram was drawn to construct the intersection target interactions network by referring to the STRING database. Topological analysis of the protein interaction network was performed using Cytoscape 3.7.2 software to screen the core HQD targets for CRC. The core targets were imported into the DAVID 6.8 analysis website for gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses and visualization. Finally, molecular docking was performed using AutoDockTool and PyMOL for validation.
RESULTS In total, 280 potential drug-active ingredients were present in HQD, including 1474 targets of the drug-active ingredients. The main active ingredients identified were betulin, tetrahydropalmatine, and quercetin. In total, 10249 CRC-related targets and 1014 drug-disease intersecting targets were identified, including 28 core targets of action such as Jun proto-oncogene, AP-1 transcription factor subunit, signal transducer and activator of transcription 3, tumor protein p53, vascular endothelial growth factor, and AKT serine/threonine kinase 1. The gene ontology enrichment functional analysis yielded 503 enrichment results, including 406 biological processes that were mainly related to the positive regulation of both gene expression and transcription and cellular response to hypoxia, etc. In total, 38 cellular components were primarily related to polymer complexes, transcription factor complexes, and platelet alpha granule lumen. Then, 59 molecular functions were closely related to the binding of enzymes, homologous proteins, and transcription factors. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis yielded 139 enrichment results, involving epidermal growth factor receptor tyrosine kinase inhibitor resistance and HIF-1 and mitogen-activated protein kinase signaling pathways.
CONCLUSION HQD can play a role in CRC treatment through the “multi-component-target–pathway”. The active ingredients betulin, tetrahydropalmatine, and quercetin may act on targets such as Jun proto-oncogene, AP-1 transcription factor subunit, signal transducer and activator of transcription 3, tumor protein p53, vascular endothelial growth factor, and AKT serine/threonine kinase 1, which in turn regulate HIF-1 and mitogen-activated protein kinase signaling pathways in CRC treatment. The molecular docking junction clarified that all four key target proteins could bind strongly to the main HQD active ingredients. This indicates that HQD could slow down CRC progression by modulating multiple targets and signaling pathways.
Collapse
Affiliation(s)
- Ying-Jie Li
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550005, Guizhou Province, China
| | - Dong-Xin Tang
- Digestive Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Hong-Ting Yan
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Bing Yang
- Digestive Department, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Zhu Yang
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, China
| | - Feng-Xi Long
- Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Gui Yang 550001, Guizhou Province, China
| |
Collapse
|
|
39
|
Ruiz-Malagón AJ, Hidalgo-García L, Rodríguez-Sojo MJ, Molina-Tijeras JA, García F, Diez-Echave P, Vezza T, Becerra P, Marchal JA, Redondo-Cerezo E, Hausmann M, Rogler G, Garrido-Mesa J, Rodríguez-Cabezas ME, Rodríguez-Nogales A, Gálvez J. Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response. Biomed Pharmacother 2023; 163:114760. [PMID: 37119741 DOI: 10.1016/j.biopha.2023.114760] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/13/2023] [Accepted: 04/20/2023] [Indexed: 05/01/2023] Open
Abstract
BACKGROUND and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occur in almost 80% of patients. This mutation leads to β-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines. EXPERIMENTAL APPROACH The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies. KEY RESULTS Tigecycline showed an antiproliferative activity targeting the Wnt/β-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of cytotoxic T lymphocytes (CTLs), one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the number of tumors and an amelioration of the tumorigenesis process in CAC. CONCLUSION AND IMPLICATIONS Tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.
Collapse
Affiliation(s)
- Antonio Jesús Ruiz-Malagón
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Laura Hidalgo-García
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - María Jesús Rodríguez-Sojo
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - José Alberto Molina-Tijeras
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Federico García
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Servicio Microbiología, Hospital Universitario Clínico San Cecilio, 18100 Granada, Spain; Ciber de Enfermedades Infecciosas, CiberInfecc, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Patricia Diez-Echave
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Teresa Vezza
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Patricia Becerra
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Servicio de Anatomía Patológica, Hospital Universitario Clínico San Cecilio, 18014 Granada, Spain
| | - Juan Antonio Marchal
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, E-18100 Granada, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18016, Spain
| | - Eduardo Redondo-Cerezo
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Servicio de Aparato Digestivo. Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057, Zurich, Switzerland
| | - José Garrido-Mesa
- The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
| | - María Elena Rodríguez-Cabezas
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain.
| | - Alba Rodríguez-Nogales
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Julio Gálvez
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| |
Collapse
|
|
40
|
Jangid AK, Kim S, Kim K. Polymeric biomaterial-inspired cell surface modulation for the development of novel anticancer therapeutics. Biomater Res 2023; 27:59. [PMID: 37344853 DOI: 10.1186/s40824-023-00404-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Immune cell-based therapies are a rapidly emerging class of new medicines that directly treat and prevent targeted cancer. However multiple biological barriers impede the activity of live immune cells, and therefore necessitate the use of surface-modified immune cells for cancer prevention. Synthetic and/or natural biomaterials represent the leading approach for immune cell surface modulation. Different types of biomaterials can be applied to cell surface membranes through hydrophobic insertion, layer-by-layer attachment, and covalent conjugations to acquire surface modification in mammalian cells. These biomaterials generate reciprocity to enable cell-cell interactions. In this review, we highlight the different biomaterials (lipidic and polymeric)-based advanced applications for cell-surface modulation, a few cell recognition moieties, and how their interplay in cell-cell interaction. We discuss the cancer-killing efficacy of NK cells, followed by their surface engineering for cancer treatment. Ultimately, this review connects biomaterials and biologically active NK cells that play key roles in cancer immunotherapy applications.
Collapse
Affiliation(s)
- Ashok Kumar Jangid
- Department of Chemical and Biochemical Engineering, College of Engineering, Dongguk University, Seoul, South Korea
| | - Sungjun Kim
- Department of Chemical and Biochemical Engineering, College of Engineering, Dongguk University, Seoul, South Korea
| | - Kyobum Kim
- Department of Chemical and Biochemical Engineering, College of Engineering, Dongguk University, Seoul, South Korea.
| |
Collapse
|
|
41
|
Bizoń M, Awiżeń-Panufnik Z, Sawicki W. Comparison of Interleukin-6 with Other Markers in Diagnosis of Ovarian Cancer. J Pers Med 2023; 13:980. [PMID: 37373969 DOI: 10.3390/jpm13060980] [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: 04/19/2023] [Revised: 05/26/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The lack of specific symptoms in ovarian cancer delays onset of the diagnostic process. Hence, most cases are recognized in late stages of the disease. The aim of this study was to confirm the role of Il-6 compared to other markers in diagnosis and survival in ovarian cancer. The database was collected from 13 January 2021 to 15 February 2023. In total, 101 patients with pelvic tumors with a mean age of 57.86 ± 16.39 participated in the study. In every case, CA125, HE4, CEA, CA19-9, Il-6, C-reactive protein and procalcitonin measurements were taken. Patients with ovarian borderline tumor and metastatic ovarian tumors were excluded from further analysis. Statistically significant correlations were found between diagnosis of ovarian cancer and levels of CA125, HE4, CRP, PCT and Il-6. Comparison of Il-6 with other markers revealed that longer overall survival correlated with lower values of Il-6. In the case of a higher concentration of Il-6, OS and PFS were shorter. Sensitivity and specificity of Il-6 in diagnosis of ovarian cancer were 46.8% and 77.8%, respectively, while for CA125, CRP and PCT were 76.6% and 63%; 68% and 57.5%; 36% and 77%, respectively. More investigations are needed to identify the most specific and sensitive marker for ovarian cancer.
Collapse
Affiliation(s)
- Magdalena Bizoń
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, 03-242 Warszawa, Poland
- LUX MED Oncology Hospital, sw. Wincentego 103, 03-291 Warszawa, Poland
| | - Zofia Awiżeń-Panufnik
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, 03-242 Warszawa, Poland
| | - Włodzimierz Sawicki
- Chair and Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, 03-242 Warszawa, Poland
| |
Collapse
|
|
42
|
Tang Z, Liu L, Borlak J. Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas. Clin Epigenetics 2023; 15:89. [PMID: 37208732 DOI: 10.1186/s13148-023-01500-1] [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: 11/28/2022] [Accepted: 05/03/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density. RESULTS Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients. CONCLUSION The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.
Collapse
Affiliation(s)
- Zijiao Tang
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Lu Liu
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
| |
Collapse
|
|
43
|
Rong J, Pu R, Sun H, Liu Y, Tian T, Bi H, Xia T, Zhang L, Zhang Y, Zhao Y, Zhu L. Association between the Methylation of CpG Islands in JAK-STAT Pathway-Related Genes and Colorectal Cancer. Gene 2023; 868:147357. [PMID: 36914143 DOI: 10.1016/j.gene.2023.147357] [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: 10/27/2022] [Revised: 02/21/2023] [Accepted: 03/07/2023] [Indexed: 03/13/2023]
Abstract
BACKGROUND Aberrant promoter methylation of CpG islands plays an important role in carcinogenesis. However, the association between the DNA methylation of JAK-STAT pathway-related genes in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility remains unclear. METHODS We conducted a case-control study of 403 patients with CRC and 419 cancer free controls, and the DNA methylation levels of JAK2, STAT1, STAT3, and SOCS3 in peripheral blood samples from all subjects were assessed using a methylation-sensitive high-resolution melting (MS-HRM) analysis. RESULTS Compared with controls, the methylation of the JAK2, STAT1 and SOCS3 genes increased the CRC risk (ORadjusted=1.96, 95% CI, 1.12-3.41, P=0.01; ORadjusted=5.37, 95% CI, 3.74-7.71, P<0.01; ORadjusted=3.30, 95% CI, 1.58-6.87, P<0.01). In the multiple CpG site methylation (MCSM) analysis, a high MCSM value denoted an increased CRC risk (ORadjusted=4.97, 95% CI, 3.34-7.37, P<0.01). CONCLUSION In peripheral blood, the methylation of JAK2, STAT1, and high levels of MCSM are promising biomarkers for CRC risk.
Collapse
Affiliation(s)
- Jiesheng Rong
- Second Department of Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Rui Pu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tian Tian
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Haoran Bi
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tingting Xia
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
| | - Lin Zhu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
| |
Collapse
|
|
44
|
Bissani Gasparin C, Pilger DA. 8‐Hydroxyquinoline, Derivatives and Metal‐Complexes: A Review of Antileukemia Activities. ChemistrySelect 2023. [DOI: 10.1002/slct.202204219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Affiliation(s)
- Carolina Bissani Gasparin
- Laboratório de Análises Bioquímicas e Citológicas (LABC) Departamento de Análises Faculdade de Farmácia Universidade Federal do Rio Grande do Sul (UFRGS) Av. Ipiranga 2752, Bairro Santana CEP 90610–000 Porto Alegre RS Brazil
| | - Diogo André Pilger
- Laboratório de Análises Bioquímicas e Citológicas (LABC) Departamento de Análises Faculdade de Farmácia Universidade Federal do Rio Grande do Sul (UFRGS) Av. Ipiranga 2752, Bairro Santana CEP 90610–000 Porto Alegre RS Brazil
- Postgraduate Program in Pharmaceutical Sciences Universidade Federal do Rio Grande do Sul (UFRGS) Av. Ipiranga 2752, Bairro Santana CEP 90610–000 Porto Alegre RS Brazil
| |
Collapse
|
|
45
|
Byun WS, Lim H, Hong J, Bae ES, Lee SB, Kim Y, Lee J, Lee SK, Hong S. Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer. J Med Chem 2023; 66:3106-3133. [PMID: 36786551 DOI: 10.1021/acs.jmedchem.2c01115] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Metastatic triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based on marinacarboline (MC), a series β-carboline derivatives were synthesized and investigated for their antitumor activities against docetaxel-resistant MDA-MB-231 (MDA-MB-231-DTR) cells. Combining antiproliferation and STAT3 inhibitory activities, MC0704 was selected as the most promising β-carboline compound. MC0704 effectively impeded the metastatic potential of MDA-MB-231-DTR cells in vitro, and the combination of MC0704 and docetaxel exhibited potent antitumor activities in a xenograft mouse model. These findings suggested that MC0704 can be a lead candidate as a target therapeutic agent for TNBC patients with docetaxel resistance.
Collapse
Affiliation(s)
- Woong Sub Byun
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.,Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyewon Lim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Junhwa Hong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Eun Seo Bae
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seok Beom Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Younggwan Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeeyeon Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Sang Kook Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Suckchang Hong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| |
Collapse
|
|
46
|
Merhi M, Ahmad F, Taib N, Inchakalody V, Uddin S, Shablak A, Dermime S. The complex network of transcription factors, immune checkpoint inhibitors and stemness features in colorectal cancer: A recent update. Semin Cancer Biol 2023; 89:1-17. [PMID: 36621515 DOI: 10.1016/j.semcancer.2023.01.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/19/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.
Collapse
Affiliation(s)
- Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Fareed Ahmad
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Nassiba Taib
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Inchakalody
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Alaaeldin Shablak
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
| |
Collapse
|
|
47
|
Taheri F, Ebrahimi SO, Heidari R, Pour SN, Reiisi S. Mechanism and function of miR-140 in human cancers: A review and in silico study. Pathol Res Pract 2023; 241:154265. [PMID: 36509008 DOI: 10.1016/j.prp.2022.154265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/27/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022]
Abstract
MicroRNA-140 (miR-140) acts as a tumor suppressor and plays a vital role in cell biological functions such as cell proliferation, apoptosis, and DNA repair. The expression of this miRNA has been shown to be considerably decreased in cancer tissues and cell lines compared with normal adjacent tissues. Consequently, aberrant expression of some miR-140 target genes can lead to the initiation and progression of various human cancers, such as breast cancer, gastrointestinal cancers, lung cancer, and prostate cancer. The dysregulation of the miR-140 network also affects cell proliferation, invasion, metastasis, and apoptosis of cancer cells by affecting various signaling pathways. Besides, up-regulation of miR-140 could enhance the efficacy of chemotherapeutic agents in different cancer. We aimed to cover most aspects of miR-140 function in cancer development and address its importance in different stages of cancer progression.
Collapse
Affiliation(s)
- Forough Taheri
- Department of Genetics, Sharekord Branch, Islamic Azad University, Sharekord, Iran
| | - Seyed Omar Ebrahimi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
| | - Razieh Heidari
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Somaye Nezamabadi Pour
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Somayeh Reiisi
- Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran.
| |
Collapse
|
|
48
|
Gulubova MV, Chonov DC, Ivanova KV, Hristova MK, Krasimirova-Ignatova MM, Vlaykova TI. Intratumoural expression of IL-6/STAT3, IL-17 and FOXP3 immune cells in the immunosuppressive tumour microenvironment of colorectal cancer Immune cells-positive for IL-6, STAT3, IL-17 and FOXP3 and colorectal cancer development. BIOTECHNOL BIOTEC EQ 2022. [DOI: 10.1080/13102818.2022.2072765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
| | - Dimitur Chavdarov Chonov
- Department of General and Operative Surgery, Trakia University, Medical Faculty, Stara Zagora Bulgaria
- Ward of Operative Surgery, University Hospital “Prof. D-r Stoyan Kirkovich”, Stara Zagora, Bulgaria
| | - Koni Vancho Ivanova
- Department of Pathology, Trakia University, Medical Faculty, Stara Zagora, Bulgaria
| | | | | | - Tatyana Ivanova Vlaykova
- Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| |
Collapse
|
|
49
|
Zhu Z, McGray AJR, Jiang W, Lu B, Kalinski P, Guo ZS. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer 2022; 21:196. [PMID: 36221123 PMCID: PMC9554963 DOI: 10.1186/s12943-022-01664-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.
Collapse
Affiliation(s)
- Zhi Zhu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - A J Robert McGray
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Weijian Jiang
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Binfeng Lu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pawel Kalinski
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| | - Zong Sheng Guo
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| |
Collapse
|
|
50
|
Nintedanib induces senolytic effect via STAT3 inhibition. Cell Death Dis 2022; 13:760. [PMID: 36055997 PMCID: PMC9440251 DOI: 10.1038/s41419-022-05207-8] [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: 01/31/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 01/21/2023]
Abstract
Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing RS. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity. Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts. Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.
Collapse
|