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Ozel B, Kipcak S, Caglar HO, Kayabasi C, Goker Bagca B, Gunduz C, Selvi Gunel N, Biray Avci C. PI3K/mTOR Inhibitor VS-5584 Alters Expression of WNT Signaling Genes and Induces Apoptosis in Lung Adenocarcinoma Cells: In Vitro and In Silico Insight. Cell Biochem Biophys 2025; 83:2313-2322. [PMID: 39690396 DOI: 10.1007/s12013-024-01643-9] [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] [Accepted: 12/05/2024] [Indexed: 12/19/2024]
Abstract
Lung cancer (LC) accounts for approximately 25% of all cancer cases, with 80-85% of these being non-small cell lung cancer (NSCLC). VS-5584 is a novel anti-cancer agent that specifically inhibits mTORC1/2 and class I PI3K isoforms. There is cross-talk between the PI3K-Akt-mTOR and WNT signaling pathways that are abnormally activated in NSCLC. In this study, we aimed to evaluate the anti-cancer effects of VS-5584 on A549 lung adenocarcinoma cells and changes in WNT signaling gene expression in vitro, while also correlating differentially expressed genes in silico. The effect of VS-5584 on A549 cell viability was assessed by the MTT assay. Apoptosis and cell cycle profiles were analyzed by flow cytometry, while WNT signaling gene expression was measured by quantitative RT-PCR. Differentially expressed genes (DEGs) in the TCGA LUAD and LUSC datasets were identified using the GEPIA2 platform. VS-5584 treatment induced apoptosis and caused cell cycle arrest at the G0/G1 phase in A549 cells. The mRNA expression levels of WNT signaling genes significantly decreased in treated cells. The expression of some upregulated DEGs in the datasets decreased in A549 cells treated with VS-5584. VS-5584 shows promise as an anti-cancer agent in the treatment of NSCLC by downregulating the expression of WNT signaling genes.
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Affiliation(s)
- Buket Ozel
- Ege University, Faculty of Medicine, Medical Biology Department, Izmir, Turkey
| | - Sezgi Kipcak
- Ege University, Faculty of Medicine, Medical Biology Department, Izmir, Turkey
| | - Hasan Onur Caglar
- Department of Molecular Biology and Genetics, Science Faculty, Erzurum Technical University, Erzurum, Turkey
| | - Cagla Kayabasi
- Balıkesir University, Faculty of Medicine, Medical Biology Department, Balıkesir, Turkey
| | - Bakiye Goker Bagca
- Aydın Adnan Menderes University, Faculty of Medicine, Medical Biology Department, Aydın, Turkey
| | - Cumhur Gunduz
- Ege University, Faculty of Medicine, Medical Biology Department, Izmir, Turkey
| | - Nur Selvi Gunel
- Ege University, Faculty of Medicine, Medical Biology Department, Izmir, Turkey
| | - Cigir Biray Avci
- Ege University, Faculty of Medicine, Medical Biology Department, Izmir, Turkey.
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Ismail DF, El-Keey MM, Elgendy SM, Hessien M. Impregnation of mesenchymal stem cell conditioned media with wortmannin enhanced its antiproliferative effect in breast cancer cells via PI3K/Akt/mTOR pathway. BMC Res Notes 2025; 18:93. [PMID: 40038752 PMCID: PMC11877855 DOI: 10.1186/s13104-025-07124-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 01/24/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND/AIM Conditioned media derived from Mesenchymal stem cells (MSC-CM) was suggested as a promising alternative cell-free regenerative therapy. It is hypothesized that the synergistic effect of MSC-CM with anticancer drugs may improve their antiproliferative and antimetastatic effects against cancer cells. Herein, the MSC-CM was impregnated with Wortmannin, a pan-PI3K/Akt/mTOR inhibitor, and their combined effect was investigated against breast cancer cells. MATERIALS AND METHODS To explore this, the cytotoxic, apoptotic, and autophagic potentials were assessed in luminal-A breast cancer cells (MCF-7). RESULTS We found that incubation of MCF-7 to Wort-containing-CM induced apoptosis- and autophagy-mediated cell death, meanwhile prolonged exposure caused massive necrotic cell death. The involvement of MSC-CM effectively reduced Wortmannin IC50 observed in Wort-treated cells. Also, Wort-loaded-CM induced nuclear DNA fragmentation and reduced in vitro cell migration. These findings were associated with a Wort-dependent reduction in cell viability, the formation of the phosphorylated Akt and mTOR proteins, reduced the expression of mRNA, and downregulated the expression of the catalytic domain of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K-Ca). CONCLUSION These findings revealed the promising antiproliferative and antimetastasis effects of combining pan-PI3K/Akt/mTOR inhibitors with MSC-derived-CM in breast cancer via the downregulation of PI3K/AKT/mTOR signaling pathways. Further studies are required to validate this chem-regenerative strategy in cancer treatment.
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Affiliation(s)
- Doha F Ismail
- Molecular Cell Biology Unit, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Mai M El-Keey
- Molecular Cell Biology Unit, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Saad M Elgendy
- Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed Hessien
- Molecular Cell Biology Unit, Division of Biochemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
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Saleh AA, Elghobashy YA, Kasemy ZA, Hegazy A, ALrefai AA. Impact of Dysregulated LINC01559 and LINC01410 Expression on the Diagnosis and Survival of Non-Small Cell Lung Cancer. Biochem Genet 2024; 62:4011-4026. [PMID: 38265621 DOI: 10.1007/s10528-023-10632-1] [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: 07/19/2023] [Accepted: 12/12/2023] [Indexed: 01/25/2024]
Abstract
Lung cancer is a widely recognized cancer with a very low survival rate, as it is mostly diagnosed at advanced stages. The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC). LncRNAs are widely involved in cancer progression and migration. Therefore, we intended to estimate the circulatory expression levels of LINC01559 and LINC01410 in NSCLC and their roles in tumor prognosis evaluation as less invasive potential markers. The relative expression levels of the plasma cell-free lncRNAs LINC01559 and LINC01410 in seventy patients with NSCLC and seventy healthy subjects as controls were measured by real-time PCR. Enzyme-linked immunosorbent assays were utilized to measure carcinoembryonic antigen (CEA) concentrations. The LINC01559 and LINC01410 expression levels were significantly increased in NSCLC patients versus controls. Both lncRNAs showed good performance in the ROC curve analysis with high sensitivity and specificity for distinguishing patients from controls. LINC01559 had the highest AUC in the ROC curve analysis (0.96, 95 CI% CI: 0.93-0.99) for distinguishing patients from controls, while LINC01410 had the highest AUC (0.77, 95 CI% CI: 0.65-0.89) for differentiating metastatic tumors from nonmetastatic tumors. High expression levels of LINC01410 and LINC01559 were associated with low overall survival (log rank = 47.04 and 28.18, respectively, P < 0.001) and low progression-free survival (log rank = 40.68 and 28.77, respectively (P < 0.001)) and with the presence of metastasis. We suggest that LINC01559 and LINC01410 can be used as valuable, high-performing biomarkers in NSCLC diagnosis and prognosis prediction.
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Affiliation(s)
- Amany A Saleh
- Faculty of Medicine, Medical Biochemistry & Molecular Biology Department, Menoufia University, Shibin Al Kawm, Egypt.
- Medical Surgical Nursing Department, College of Nursing, Taibah University, Medina, Saudi Arabia.
| | - Yasser A Elghobashy
- Faculty of Medicine, Medical Biochemistry & Molecular Biology Department, Menoufia University, Shibin Al Kawm, Egypt
| | - Zeinab A Kasemy
- Faculty of Medicine, Public Health and Community Medicine Department, Menoufia University, Shibin Al Kawm, Egypt
| | - Amira Hegazy
- Faculty of Medicine, Clinical Oncology and Nuclear Medicine Department, Menoufia University, Shibin Al Kawm, Egypt
| | - Abeer A ALrefai
- Faculty of Medicine, Medical Biochemistry & Molecular Biology Department, Menoufia University, Shibin Al Kawm, Egypt
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Blanchard CE, Gomeiz AT, Avery K, Gazzah EE, Alsubaie AM, Sikaroodi M, Chiari Y, Ward C, Sanchez J, Espina V, Petricoin E, Baldelli E, Pierobon M. Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds. Cell Commun Signal 2024; 22:377. [PMID: 39061010 PMCID: PMC11282632 DOI: 10.1186/s12964-024-01742-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Tumor heterogeneity is a main contributor of resistance to anti-cancer targeted agents though it has proven difficult to study. Unfortunately, model systems to functionally characterize and mechanistically study dynamic responses to treatment across coexisting subpopulations of cancer cells remain a missing need in oncology. METHODS Using single cell cloning and expansion techniques, we established monoclonal cell subpopulations (MCPs) from a commercially available epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer cell line. We then used this model sensitivity to the EGFR inhibitor osimertinib across coexisting cell populations within the same tumor. Pathway-centered signaling dynamics associated with response to treatment and morphological characteristics of the MCPs were assessed using Reverse Phase Protein Microarray. Signaling nodes differentially activated in MCPs less sensitive to treatment were then pharmacologically inhibited to identify target signaling proteins putatively implicated in promoting drug resistance. RESULTS MCPs demonstrated highly heterogeneous sensitivities to osimertinib. Cell viability after treatment increased > 20% compared to the parental line in selected MCPs, whereas viability decreased by 75% in other MCPs. Reduced treatment response was detected in MCPs with higher proliferation rates, EGFR L858R expression, activation of EGFR binding partners and downstream signaling molecules, and expression of epithelial-to-mesenchymal transition markers. Levels of activation of EGFR binding partners and MCPs' proliferation rates were also associated with response to c-MET and IGFR inhibitors. CONCLUSIONS MCPs represent a suitable model system to characterize heterogeneous biomolecular behaviors in preclinical studies and identify and functionally test biological mechanisms associated with resistance to targeted therapeutics.
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Affiliation(s)
- Claire E Blanchard
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Alison T Gomeiz
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Kyle Avery
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Emna El Gazzah
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Abduljalil M Alsubaie
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, VA, 20110, USA
| | - Ylenia Chiari
- Department of Biology, George Mason University, Fairfax, VA, 22030, USA
- School of Life Sciences, University of Nottingham, Nottingham, NG7 2TQ, UK
| | - Chelsea Ward
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Jonathan Sanchez
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Emanuel Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Elisa Baldelli
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Mariaelena Pierobon
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA.
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA.
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Schulz JA, Hartz AMS, Bauer B. ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery. Pharmacol Rev 2023; 75:815-853. [PMID: 36973040 PMCID: PMC10441638 DOI: 10.1124/pharmrev.120.000025] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/29/2023] Open
Abstract
The drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regulation mechanisms that control these transporters, is critical to solving this clinical problem.In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier research and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood-brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their potential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS disease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be targeted for therapeutic purposes in the clinic. SIGNIFICANCE STATEMENT: The ABCB1/ABCG2 drug efflux system at the blood-brain barrier poses a significant problem to successful drug delivery to the brain. The article reviews signaling pathways that regulate blood-brain barrier ABCB1/ABCG2 and could potentially be targeted for therapeutic purposes.
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Affiliation(s)
- Julia A Schulz
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
| | - Anika M S Hartz
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
| | - Björn Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy (J.A.S., B.B.), Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, College of Medicine (A.M.S.H.), University of Kentucky, Lexington, Kentucky
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de Kort WWB, de Ruiter EJ, Haakma WE, Driehuis E, Devriese LA, van Es RJJ, Willems SM. p-mTOR, p-ERK and PTEN Expression in Tumor Biopsies and Organoids as Predictive Biomarkers for Patients with HPV Negative Head and Neck Cancer. Head Neck Pathol 2023; 17:697-707. [PMID: 37486536 PMCID: PMC10514008 DOI: 10.1007/s12105-023-01576-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND Survival rates of head and neck squamous cell carcinoma (HNSCC) have only marginally improved in the last decades. Hence there is a need for predictive biomarkers for long-time survival that can help to guide treatment decisions and might lead to the development of new therapies. The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is the most frequently altered pathway in HNSCC, genes are often mutated, amplificated and overexpressed causing aberrant signaling affecting cell growth and differentiation. Numerous genetic alterations of upstream and downstream factors have currently been clarified. However, their predictive value has yet to be established. Therefore we assess the predictive value of p-mTOR, p-ERK and PTEN expression. METHODS Tissue microarrays (TMA's) of HPV-negative patients with oropharyngeal (n = 48), hypopharyngeal (n = 16) or laryngeal (n = 13) SCC, treated with primary chemoradiation (cisplatin/carboplatin/cetuximab and radiotherapy), were histologically stained for p-mTOR, PTEN and p-ERK. Expression was correlated to overall survival (OS), disease free survival (DFS) and locoregional control (LRC). Also p-mTOR was histologically stained in a separate cohort of HNSCC organoids (n = 8) and correlated to mTOR-inhibitor everolimus response. RESULTS High p-mTOR expression correlated significantly with worse OS in multivariate analysis in the whole patient cohort [Hazar Ratio (HR) 1.06, 95%CI 1.01-1.11, p = 0.03] and in the cisplatin/carboplatin group with both worse OS (HR 1.09, 95%CI 1.02-1.16, p = 0.02) and DFS (HR 1.06, 95%CI 1.00-1.12, p = 0,04). p-ERK expression correlated significantly with DFS in univariate analysis in the whole patient cohort (HR 1.03, 95%CI 1.00-1.05, p = 0.04) and cisplatin/carboplatin group (HR 1.03, 95%CI 1.00-1.07, p = 0.04). PTEN-expression did not correlate with OS/DFS/LRC. Better organoid response to everolimus correlated significantly to higher p-mTOR expression (Rs = - 0.731, p = 0.04). CONCLUSIONS High p-mTOR expression predicts and high p-ERK expression tends to predict worse treatment outcome in HPV negative HNSCC patients treated with chemoradiation, providing additional evidence that these markers are candidate prognostic biomarkers for survival in this patient population. Also this study shows that the use of HNSCC organoids for biomarker research has potential. The role of PTEN expression as prognostic biomarker remains unclear, as consistent evidence on its prognostic and predictive value is lacking.
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Affiliation(s)
- W. W. B. de Kort
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - E. J. de Ruiter
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - W. E. Haakma
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - E. Driehuis
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands
| | - L. A. Devriese
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - R. J. J. van Es
- Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Head and Neck Surgical Oncology, Utrecht Cancer Center, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - S. M. Willems
- Department of Pathology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
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Gargalionis AN, Papavassiliou KA, Papavassiliou AG. Implication of mTOR Signaling in NSCLC: Mechanisms and Therapeutic Perspectives. Cells 2023; 12:2014. [PMID: 37566093 PMCID: PMC10416991 DOI: 10.3390/cells12152014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/28/2023] [Accepted: 08/06/2023] [Indexed: 08/12/2023] Open
Abstract
Mechanistic target of the rapamycin (mTOR) signaling pathway represents a central cellular kinase that controls cell survival and metabolism. Increased mTOR activation, along with upregulation of respective upstream and downstream signaling components, have been established as oncogenic features in cancer cells in various tumor types. Nevertheless, mTOR pathway therapeutic targeting has been proven to be quite challenging in various clinical settings. Non-small cell lung cancer (NSCLC) is a frequent type of solid tumor in both genders, where aberrant regulation of the mTOR pathway contributes to the development of oncogenesis, apoptosis resistance, angiogenesis, cancer progression, and metastasis. In this context, the outcome of mTOR pathway targeting in clinical trials still demonstrates unsatisfactory results. Herewith, we discuss recent findings regarding the mechanisms and therapeutic targeting of mTOR signaling networks in NSCLC, as well as future perspectives for the efficient application of treatments against mTOR and related protein molecules.
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Affiliation(s)
- Antonios N. Gargalionis
- Department of Biopathology, ‘Eginition’ Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Kostas A. Papavassiliou
- First University Department of Respiratory Medicine, ‘Sotiria’ Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Ursino C, Mouric C, Gros L, Bonnefoy N, Faget J. Intrinsic features of the cancer cell as drivers of immune checkpoint blockade response and refractoriness. Front Immunol 2023; 14:1170321. [PMID: 37180110 PMCID: PMC10169604 DOI: 10.3389/fimmu.2023.1170321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Immune checkpoint blockade represents the latest revolution in cancer treatment by substantially increasing patients' lifetime and quality of life in multiple neoplastic pathologies. However, this new avenue of cancer management appeared extremely beneficial in a minority of cancer types and the sub-population of patients that would benefit from such therapies remain difficult to predict. In this review of the literature, we have summarized important knowledge linking cancer cell characteristics with the response to immunotherapy. Mostly focused on lung cancer, our objective was to illustrate how cancer cell diversity inside a well-defined pathology might explain sensitivity and refractoriness to immunotherapies. We first discuss how genomic instability, epigenetics and innate immune signaling could explain differences in the response to immune checkpoint blockers. Then, in a second part we detailed important notions suggesting that altered cancer cell metabolism, specific oncogenic signaling, tumor suppressor loss as well as tight control of the cGAS/STING pathway in the cancer cells can be associated with resistance to immune checkpoint blockade. At the end, we discussed recent evidences that could suggest that immune checkpoint blockade as first line therapy might shape the cancer cell clones diversity and give rise to the appearance of novel resistance mechanisms.
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Affiliation(s)
| | | | | | | | - Julien Faget
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Univ Montpellier, Institut du Cancer de Montpellier (ICM), Montpellier, France
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Alam M, Hasan GM, Eldin SM, Adnan M, Riaz MB, Islam A, Khan I, Hassan MI. Investigating regulated signaling pathways in therapeutic targeting of non-small cell lung carcinoma. Biomed Pharmacother 2023; 161:114452. [PMID: 36878052 DOI: 10.1016/j.biopha.2023.114452] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/19/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
Non-small cell lung carcinoma (NSCLC) is the most common malignancy worldwide. The signaling cascades are stimulated via genetic modifications in upstream signaling molecules, which affect apoptotic, proliferative, and differentiation pathways. Dysregulation of these signaling cascades causes cancer-initiating cell proliferation, cancer development, and drug resistance. Numerous efforts in the treatment of NSCLC have been undertaken in the past few decades, enhancing our understanding of the mechanisms of cancer development and moving forward to develop effective therapeutic approaches. Modifications of transcription factors and connected pathways are utilized to develop new treatment options for NSCLC. Developing designed inhibitors targeting specific cellular signaling pathways in tumor progression has been recommended for the therapeutic management of NSCLC. This comprehensive review provided deeper mechanistic insights into the molecular mechanism of action of various signaling molecules and their targeting in the clinical management of NSCLC.
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Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Sayed M Eldin
- Center of Research, Faculty of Engineering, Future University in Egypt, New Cairo 11835, Egypt
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Muhammad Bilal Riaz
- Faculty of Applied Physics and Mathematics, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdnask, Poland; Department of Computer Science and Mathematics, Lebanese American University, Byblos, Lebanon
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Ilyas Khan
- Department of Mathematics, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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Yue YL, Zhang MY, Liu JY, Fang LJ, Qu YQ. The role of autophagy in idiopathic pulmonary fibrosis: from mechanisms to therapies. Ther Adv Respir Dis 2022; 16:17534666221140972. [PMID: 36468453 PMCID: PMC9726854 DOI: 10.1177/17534666221140972] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial pulmonary disease with an extremely poor prognosis. Autophagy is a fundamental intracellular process involved in maintaining cellular homeostasis and regulating cell survival. Autophagy deficiency has been shown to play an important role in the progression of pulmonary fibrosis. This review focused on the six steps of autophagy, as well as the interplay between autophagy and other seven pulmonary fibrosis related mechanisms, which include extracellular matrix deposition, myofibroblast differentiation, epithelial-mesenchymal transition, pulmonary epithelial cell dysfunction, apoptosis, TGF-β1 pathway, and the renin-angiotensin system. In addition, this review also summarized autophagy-related signaling pathways such as mTOR, MAPK, JAK2/STAT3 signaling, p65, and Keap1/Nrf2 signaling during the development of IPF. Furthermore, this review also illustrated the commonly used autophagy detection methods, the currently approved antifibrotic drugs pirfenidone and nintedanib, and several prospective compounds targeting autophagy for the treatment of IPF.
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Affiliation(s)
- Yue-Liang Yue
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Meng-Yu Zhang
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Jian-Yu Liu
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Li-Jun Fang
- Shandong Key Laboratory of Infectious Respiratory Diseases, Laboratory of Basic Medical Sciences, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
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Zu Y, Wang D, Ping W, Sun W. The roles of CPSF6 in proliferation, apoptosis and tumorigenicity of lung adenocarcinoma. Aging (Albany NY) 2022; 14:9300-9316. [PMID: 36446361 PMCID: PMC9740356 DOI: 10.18632/aging.204407] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 10/27/2022] [Indexed: 11/30/2022]
Abstract
Cleavage and polyadenylation specific factor 6 (CPSF6), a member of serine/arginine-rich protein family, is implicated in HIV-1-infection and replication. Overexpression of CPSF6 predicts poor prognostic outcomes of breast cancer. However, the expression and possible function of CPSF6 in lung adenocarcinoma (LUAD) still needs to be explored. Here, we found that CPSF6 is significantly higher expressed in tumor tissues than normal tissues in multiple cancer types. Besides, CPSF6 plays a significant risky role in LUAD that is associated with overall survival (HR=1.337, P=0.051) and disease-specific survival (HR=1.4739, P=0.042). CPSF6 mRNA was up-regulated in LUAD tissues by analyzing publicly available datasets from Gene Expression Omnibus (GEO). Further survival analysis on The Cancer Genome Atlas (TCGA) dataset suggested a close correlation between CPSF6 expression and overall survival, and disease-free survival of LUAD patients. Inhibition of CPSF6 expression by lentivirus-mediated RNA interference (RNAi) in two LUAD cell lines (A549 and NCH-H1299) caused a significant reduction in cell proliferation, colony formation and a notable induction in apoptotic rate. CPSF6 knockdown in xenograft tumors inhibited LUAD cell growth in vivo. Moreover, we identified differentially expressed genes with CPSF6 inhibition by Microarray analysis, and pathway analyses revealed that CPSF6 knockdown resulted in the dysregulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Collectively, our results are the first to demonstrate that CPSF6 functions as an oncoprotein by regulating cancer-related pathways in LUAD.
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Affiliation(s)
- Yukun Zu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dao Wang
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei Ping
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei Sun
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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12
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Kouokam JC, Meaza I, Wise JP. Inflammatory effects of hexavalent chromium in the lung: A comprehensive review. Toxicol Appl Pharmacol 2022; 455:116265. [PMID: 36208701 PMCID: PMC10024459 DOI: 10.1016/j.taap.2022.116265] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/23/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022]
Abstract
Besides smoking, lung cancer can be caused by other factors, including heavy metals such as cadmium, nickel, arsenic, beryllium and hexavalent chromium [Cr(VI)], which is used in multiple settings, resulting in widespread environmental and occupational exposures as well as heavy use. The mechanism by which Cr(VI) causes lung cancer is not completely understood. Currently, it is admitted chromosome instability is a key process in the mechanism of Cr(VI)-induced cancer, and previous studies have suggested Cr(VI) impacts the lung tissue in mice by triggering tissue damage and inflammation. However, the mechanism underlying Cr(VI)-induced inflammation and its exact role in lung cancer are unclear. Therefore, this review aimed to systematically examine previous studies assessing Cr(VI)-induced inflammation and to summarize the major inflammatory pathways involved in Cr(VI)-induced inflammation. In cell culture studies, COX2, VEGF, JAK-STAT, leukotriene B4 (LTB4), MAPK, NF-ҡB and Nrf2 signaling pathways were consistently upregulated by Cr(VI), clearly demonstrating that these pathways are involved in Cr(VI)-induced inflammation. In addition, Akt signaling was also shown to contribute to Cr(VI)-induced inflammation, although discrepant findings were reported. Few mechanistic studies were performed in animal models, in which Cr(VI) upregulated oxidative pathways, NF-kB signaling and the MAPK pathway in the lung tissue. Similar to cell culture studies, opposite effects of Cr(VI) on Akt signaling were reported. This work provides insights into the mechanisms by which Cr(VI) induces lung inflammation. However, discrepant findings and other major issues in study design, both in cell and animal models, suggest that further studies are required to unveil the mechanism of Cr(VI)-induced inflammation and its role in lung cancer.
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Affiliation(s)
- J Calvin Kouokam
- Wise Laboratory of Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville, 500 S Preston St, Rm 1422, Louisville, KY, USA.
| | - Idoia Meaza
- Wise Laboratory of Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville, 500 S Preston St, Rm 1422, Louisville, KY, USA
| | - John Pierce Wise
- Wise Laboratory of Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville, 500 S Preston St, Rm 1422, Louisville, KY, USA
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13
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Lv L, Huang RH, Li J, Xu J, Gao W. Impact of NSCLC metabolic remodeling on immunotherapy effectiveness. Biomark Res 2022; 10:66. [PMID: 36038935 PMCID: PMC9425942 DOI: 10.1186/s40364-022-00412-1] [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: 05/31/2022] [Accepted: 08/12/2022] [Indexed: 11/10/2022] Open
Abstract
It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy’s effectiveness in NSCLC.
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Affiliation(s)
- Lulu Lv
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Ruo Han Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Jiale Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Jing Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Wen Gao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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14
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Relationship Between the MicroRNAs and PI3K/AKT/mTOR Axis: Focus on Non-Small Cell Lung Cancer. Pathol Res Pract 2022; 239:154093. [DOI: 10.1016/j.prp.2022.154093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/21/2022]
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15
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Leung JH, Ng B, Lim WW. Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer. Cells 2022; 11:cells11142257. [PMID: 35883698 PMCID: PMC9318853 DOI: 10.3390/cells11142257] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 02/01/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and is a fast progressive disease when left untreated. Identification of potential biomarkers in NSCLC is an ongoing area of research that aims to detect, diagnose, and prognosticate patients early to optimize treatment. We review the role of interleukin-11 (IL11), a stromal-cell derived pleiotropic cytokine with profibrotic and cellular remodeling properties, as a potential biomarker in NSCLC. This review identifies the need for biomarkers in NSCLC, the potential sources of IL11, and summarizes the available information leveraging upon published literature, publicly available datasets, and online tools. We identify accumulating evidence suggesting IL11 to be a potential biomarker in NSCLC patients. Further in-depth studies into the pathophysiological effects of IL11 on stromal-tumor interaction in NSCLC are warranted and current available literature highlights the potential value of IL11 detection as a diagnostic and prognostic biomarker in NSCLC.
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Affiliation(s)
- Jason Hongting Leung
- Department of Cardiothoracic Surgery, National Heart Center Singapore, Singapore 169609, Singapore
- Correspondence:
| | - Benjamin Ng
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore; (B.N.); (W.-W.L.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169609, Singapore
| | - Wei-Wen Lim
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore; (B.N.); (W.-W.L.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169609, Singapore
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16
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Sanaei MJ, Razi S, Pourbagheri-Sigaroodi A, Bashash D. The PI3K/Akt/mTOR pathway in lung cancer; oncogenic alterations, therapeutic opportunities, challenges, and a glance at the application of nanoparticles. Transl Oncol 2022; 18:101364. [PMID: 35168143 PMCID: PMC8850794 DOI: 10.1016/j.tranon.2022.101364] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/15/2022] [Accepted: 02/05/2022] [Indexed: 12/20/2022] Open
Abstract
Lung cancer is the most common and deadliest human malignancies. The alterations of PI3K/Akt/mTOR pathway are related to lung cancer progression. PI3K axis regulates proliferation, apoptosis, metastasis, and EMT of lung cancer. Agents inhibiting components of PI3K axis diminish lung tumor growth and invasion. Low efficacy and off-target toxicity could be improved by nanoparticle application. Lung cancer is the leading cause of cancer-related mortality worldwide. Although the PI3K/Akt/mTOR signaling pathway has recently been considered as one of the most altered molecular pathways in this malignancy, few articles reviewed the task. In this review, we aim to summarize the original data obtained from international research laboratories on the oncogenic alterations in each component of the PI3K/Akt/mTOR pathway in lung cancer. This review also responds to questions on how aberrant activation in this axis contributes to uncontrolled growth, drug resistance, sustained angiogenesis, as well as tissue invasion and metastatic spread. Besides, we provide a special focus on pharmacologic inhibitors of the PI3K/Akt/mTOR axis, either as monotherapy or in a combined-modal strategy, in the context of lung cancer. Despite promising outcomes achieved by using these agents, however, the presence of drug resistance as well as treatment-related adverse events is the other side of the coin. The last section allocates a general overview of the challenges associated with the inhibitors of the PI3K pathway in lung cancer patients. Finally, we comment on the future research aspects, especially in which nano-based drug delivery strategies might increase the efficacy of the therapy in this malignancy.
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17
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Abdik H. Antineoplastic effects of erufosine on small cell and non-small cell lung cancer cells through induction of apoptosis and cell cycle arrest. Mol Biol Rep 2022; 49:2963-2971. [PMID: 35015224 DOI: 10.1007/s11033-022-07117-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 01/04/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Lung cancer (LC) is the most common types of cancer worldwide and is marked by high mortality rate. LC is classified into two major types due to their molecular and histological properties; non-small cell lung cancer (NSCLC) A549 and small cell lung cancer (SCLC). Currently, surgery, chemotherapy and radiation therapy are the most common treatment options of LC. However, the survival rate of LC is still very poor. Therefore, new treatment strategies are urgently needed. Erufosine (ErPC3) is a novel alkylphosphocholine and inhibits the translocation of Akt to the plasma membrane. METHODS AND RESULTS In the current study, the effects of ErPC3 in NSCLC cell line A549 and SCLC cell line DMS 114 in terms of cell viability, induction of apoptosis, cell cycle phase distribution, gene and protein expression levels, and migration capacity were investigated. 25 µM ErPC3 exhibited dose-dependent cytotoxicity against in both cancer cells. However, DMS 114 was more sensitive to ErPC3 than A549. Similarly, ErPC3 induced apoptotic cell ratio in DMS114 was significantly greater than A549. 25 µM ErPC3 caused the accumulation of both cell in G2/M phase. The levels of BCL-2 were downregulated and CASPASE 3-7 and BAX were upregulated while p-Akt levels were reduced in A549 and DMS 114 cells treated with 25 µM ErPC3. Besides, ErPC3 displayed anti-migratory effect on A549 and DMS 114. CONCLUSION These findings suggest that ErPC3 may be a promising novel therapeutic candidate for treatment of LC. ErPC3 treatment merits further investigation as potential agent against LC.
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Affiliation(s)
- Hüseyin Abdik
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Sabahattin Zaim University, Istanbul, Turkey.
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Istanbul, Turkey.
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18
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Tu YC, Yeh WC, Yu HH, Lee YC, Su BC. Hedgehog Suppresses Paclitaxel Sensitivity by Regulating Akt-Mediated Phosphorylation of Bax in EGFR Wild-Type Non-Small Cell Lung Cancer Cells. Front Pharmacol 2022; 13:815308. [PMID: 35250564 PMCID: PMC8894848 DOI: 10.3389/fphar.2022.815308] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/24/2022] [Indexed: 11/30/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common and deadly cancers worldwide. Among NSCLC patients, almost half have wild-type epidermal growth factor receptor (EGFR WT). The primary therapeutic option for these EGFR WT NSCLC patients is chemotherapy, while NSCLC patients with EGFR mutations have more diverse therapeutic options, including EGFR tyrosine kinase inhibitors. Moreover, NSCLC patients with EGFR WT have worse chemotherapy response than EGFR mutant NSCLC patients. Thus, an urgent need exists for novel therapeutic strategies to improve chemotherapy response in EGFR WT NSCLC patients. Hedgehog signaling is known to be highly active in NSCLC; however, its potential role in chemoresistance is not fully understood. In the present study, we found that paclitaxel (PTX) treatment induces hedgehog signaling in EGFR WT NSCLC cells, and inhibition of hedgehog signaling with GDC-0449 (Vismodegib) increases sensitivity to PTX-stimulated apoptosis. Furthermore, GDC-0449 potentiates PTX-induced reactive oxygen species and mitochondrial dysfunction. In contrast, a hedgehog agonist, Hh-Ag1.5, attenuates PTX-induced apoptosis. Mechanistic experiments revealed that hedgehog induces phosphorylation of Akt at Ser473. Akt then phosphorylates Bax at Ser184, which can switch its activity from pro-apoptosis to anti-apoptosis. Taken together, our findings suggest that inhibition of hedgehog signaling might be a promising therapeutic strategy to improve PTX response in EGFR WT NSCLC.
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Affiliation(s)
- Yun-Chieh Tu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chen Yeh
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsin-Hsien Yu
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Cheng Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Bor-Chyuan Su
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- *Correspondence: Bor-Chyuan Su,
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19
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Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int J Mol Sci 2021; 22:ijms22147424. [PMID: 34299042 PMCID: PMC8307969 DOI: 10.3390/ijms22147424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 06/30/2021] [Accepted: 07/04/2021] [Indexed: 01/12/2023] Open
Abstract
Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520—DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2—and NCI-H23 cells—HGF, MET, COL5A2, MCM7, and GNG4—were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
- Correspondence: ; Tel.: +60-3-5514-63-45
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20
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MicroRNA-103a-3p Promotes Cell Proliferation and Invasion in Non-Small-Cell Lung Cancer Cells through Akt Pathway by Targeting PTEN. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7590976. [PMID: 34307670 PMCID: PMC8279842 DOI: 10.1155/2021/7590976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/26/2021] [Indexed: 01/01/2023]
Abstract
Background Increasing evidence has suggested that microRNA- (miR-) 103a-3p is crucial for cancer progression. However, the specific mechanism of miR-103a-3p in non-small-cell lung cancer (NSCLC) remains unclear until now. So, it is particularly urgent to clarify the mechanism between them. Methods qRT-PCR and western blot were used to measure the expression of miR-103a-3p, PTEN, Akt, and p-Akt. Cell biology experiment was applied to detect the biological function of miR-103a-3p in NSCLC cell lines. Moreover, bioinformatics analysis, luciferase reporter assay, and functional complementation analysis were carried out to investigate the target gene. Results miR-103a-3p was highly expressed in primary NSCLC samples and cell lines. miR-103a-3p mimics promoted the proliferation and invasion of NSCLC cells; miR-103a-3p inhibitor had the opposite effect. A double luciferase reporter gene experiment revealed that miR-103a-3p directly targets the PTEN mRNA 3'UTR region. siPTEN inhibited the proliferation and invasion of NSCLC cells. Further mechanistic studies showed that both overexpression of miR-103a-3p and PTEN knockdown reduced the expression of the p-Akt protein. Overexpression of PTEN partially reversed the cancer-promoting effect of miR-103a-3p. Conclusion miR-103a-3p promotes the progression of NSCLC via Akt signaling by targeting PTEN, highlighting the role of miR-103a-3p/PTEN/Akt signaling and suggesting miR-103a-3p as a novel therapeutic target for NSCLC.
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Jadhao M, Tsai EM, Yang HC, Chen YF, Liang SS, Wang TN, Teng YN, Huang HW, Wang LF, Chiu CC. The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS. Antioxidants (Basel) 2021; 10:949. [PMID: 34208283 PMCID: PMC8230873 DOI: 10.3390/antiox10060949] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/18/2022] Open
Abstract
The characteristics of phthalates had been thought to be similar to endocrine disruptors, which increases cancer risk. The role of phthalates in acquired drug resistance remains unclear. In this study, we investigated the effect of di-(2-ethylhexyl) phthalate (DEHP) on acquired drug resistance in breast cancer. MCF7 and MDA-MB-231 breast cancer cells were exposed to long-term physiological concentration of DEHP for more than three months. Long-exposure DEHP permanently attenuated the anti-proliferative effect of doxorubicin with estrogen receptor-independent activity even after withdrawal of DEHP. Long term DEHP exposure significantly reduced ROS (O2-) level in MDA-MB-231 cells while increased in MCF7 cells. ATP-binding cassette (ABC) transporters possess a widely recognized mechanism of drug resistance and are considered a target for drug therapy. Upregulation of ABC family proteins, ABCB-1 and ABCC-1 observed in DEHP-exposed clones compared to doxorubicin-resistant (DoxR) and parental MDA-MB-231 cells. A viability assay showed enhanced multidrug resistance in DEHP-exposed clones against Dox, topotecan, and irinotecan. Inhibition of ABC transporters with tariquidar, enhanced drug cytotoxicity through increased drug accumulation reversing acquired multidrug resistance in MDA-MB-231 breast cancer cells. Tariquidar enhanced Dox cytotoxicity by increasing intracellular ROS production leading to caspase-3 mediated apoptosis. Activation of PI3K/Akt signaling enhanced proliferation and growth of DEHP-exposed MDA-MB-231 cells. Overall, long-term DEHP exposure resulted in acquired multidrug resistance by upregulating ABCB-1 and ABCC1; apart from proliferation PI3K/Akt may be responsible for acquired drug resistance through ABC transporter upregulation. Targeting ABCB1 and ABCC1 with tariquidar may be a promising strategy for reversing the acquired multidrug resistance of triple-negative breast cancer cells.
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Affiliation(s)
- Mahendra Jadhao
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan; or
| | - Eing-Mei Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- The Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ho-Chun Yang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (H.-C.Y.); (S.-S.L.)
- Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 804, Taiwan;
| | - Yih-Fung Chen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Shih-Shin Liang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (H.-C.Y.); (S.-S.L.)
| | - Tsu-Nai Wang
- Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Yen-Ni Teng
- Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan;
| | - Hurng-Wern Huang
- Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung 804, Taiwan;
| | - Li-Fang Wang
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan; or
| | - Chien-Chih Chiu
- The Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (H.-C.Y.); (S.-S.L.)
- Center for Cancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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Bozinovski S, Vannitamby A, Rangamuwa K, Aujla S, Wang H, Aloe C, Irving L, Leong TT, Steinfort DP. Integrating endobronchial ultrasound bronchoscopy with molecular testing of immunotherapy biomarkers in non-small cell lung cancer. Transl Lung Cancer Res 2021; 10:2779-2787. [PMID: 34295677 PMCID: PMC8264344 DOI: 10.21037/tlcr-20-781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022]
Abstract
Immunotherapy has transformed treatment of advanced non-small-cell lung cancer (NSCLC) patients leading to remarkable long-term survival benefit. However, only about 20% of advanced NSCLC patients typically respond to immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway. The only validated biomarker for ICI therapy is the PD-L1 immunohistochemistry (IHC) test, which is considered an imperfect assay due to several variables including availability and integrity of tumour tissue, variability in staining/scoring techniques and heterogeneity in PD-L1 protein expression within and across tumour biopsies. Herein, we discuss integrating minimally invasive EBUS bronchoscopy procedures with novel molecular approaches to improve accuracy and sensitivity of PD-L1 testing. EBUS guided bronchoscopy facilitates repeated sampling of tumour tissue to increase the probability of detecting PD-L1 positive tumours. Since intra-tumoural PD-L1 (CD274) copy number is reported to be less heterogeneous than PD-L1 protein detection, quantifying PD-L1 transcript levels may increase detection of PD-L1 positive tumours. PD-L1 transcript levels show excellent concordance with PD-L1 IHC scoring and multiplex digital droplet PCR (ddPCR) assays that quantify absolute PD-L1 transcript copy number have been developed. ddPCR can also be automated for high throughput detection of low abundant variants with excellent sensitivity and accuracy to improve the broader application of diagnostic cut-off values. Optimizing diagnostic workflows that integrate optimal EBUS bronchoscopy procedures with emerging molecular ICI biomarker assays may improve the selection criteria for ICI therapy benefit.
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Affiliation(s)
- Steven Bozinovski
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Amanda Vannitamby
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Kanishka Rangamuwa
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia
| | - Savreet Aujla
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Hao Wang
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Christian Aloe
- School of Health & Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Louis Irving
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia
| | - Tracy T Leong
- Department of Respiratory Medicine, Austin Health, Heidelberg, Victoria, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Daniel P Steinfort
- Department of Respiratory Medicine, Royal Melbourne Hospital, Melbourne, Australia.,Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia
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23
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Hu Y, Wang Y, Li N, Chen L, Sun J. Discovery of novel dihydroartemisinin-cinnamic hybrids inducing lung cancer cells apoptosis via inhibition of Akt/Bad signal pathway. Bioorg Chem 2021; 111:104903. [PMID: 33894433 DOI: 10.1016/j.bioorg.2021.104903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 01/05/2023]
Abstract
A series of dihydroartemisinin-cinnamic acid hybrids were designed, synthesized and evaluated. Most of the tested compounds showed enhanced anti-proliferative activities than artemisinin and dihydroartemisinin, among which 16 g had the superior potency with IC50 values ranging from 5.07 μM to 7.88 μM against four tested cancer cell lines. The cell cycle arrest revealed that 16 g induced A549 cell cycle arrest at G0/G1 phase via regulation of G1-related protein expression (Cdk4). Further mechanism studies reveal that 16 g induced A549 cells apoptosis via inhibiting Akt/Bad pathway. Moreover, 16 g depolarized the mitochondria membrane potentials and induced ROS generation in A549. Additionally, 16 g blocked migration of A549 cells in a concentration-dependent manner. What's more, 16 g is barely nontoxic to zebrafish embryos. Overall, the cell cycle arrest, inhibition of Akt/Bad signal pathway, ROS generation and migration blocked might explain the potent anti-proliferative activities of these compounds.
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Affiliation(s)
- Yanping Hu
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Yujin Wang
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Na Li
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Li Chen
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
| | - Jianbo Sun
- State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
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24
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Zhu H, Xu Y, Li M, Chen Z. Inhibition Sequence of miR-205 Hinders the Cell Proliferation and Migration of Lung Cancer Cells by Regulating PETN-Mediated PI3K/AKT Signal Pathway. Mol Biotechnol 2021; 63:587-594. [PMID: 33783672 DOI: 10.1007/s12033-021-00321-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/20/2021] [Indexed: 01/11/2023]
Abstract
The aim of this study was to identify the pro-tumor role of miR-205 in patients with lung cancer (LC) on the cell proliferation and migration through regulating PTEN-mediated PI3K/AKT signal pathway. Paired cancer tissues and adjacent tissues were collected from 107 LC patients who received treatment in Jinan Central hospital. In addition, the purchased LC cell lines were transfected into HCC827 cell line to observe and compare the biological behaviors. Compared with adjacent tissues, miR-205 was statistically higher in LC tissues, while PTEN was notably lower (P < 0.05). Inhibition of miR-205 not only suppressed cell proliferation, migration and invasion, increased apoptosis rate, but regulated epithelial mesenchymal transformation (EMT)-related proteins. Likewise, overexpression of PETN played the same role as that of miR-205 inhibition sequence. Inhibited miR-205 or PTEN overexpression brought dramatically decreased PI3K and p-Akt. The relationship between miR-205 and PTEN was verified through the biological prediction website and luciferase reporter. Co-transfection experiments revealed that after cotransfection of miR-205 inhibitor and si-PETN, the cell proliferation and invasion showed no marked difference between cotransfection group and NC group. MiR-205 is involved in LC cell proliferation and migration by regulating PETN-mediated PI3K/AKT signal pathway, which may be a feasible treatment target for LC in clinical practice.
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Affiliation(s)
- Huizhen Zhu
- Department of Urological Surgery, Jinan Central Hospital Affiliated To Shandong University, Shandong, 250013, P.R. China
| | - Yan Xu
- Outpatient Injection Room, The First Affiliated Hospital of Shandong First Medical University, Shandong, 250014, P.R. China
| | - Meng Li
- Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong, 250013, P.R. China
| | - Zhitao Chen
- Department of Thoracic Surgery, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong, 250013, P.R. China.
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25
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Xie X, Zu X, Laster K, Dong Z, Kim DJ. 2,6-DMBQ suppresses cell proliferation and migration via inhibiting mTOR/AKT and p38 MAPK signaling pathways in NSCLC cells. J Pharmacol Sci 2021; 145:279-288. [PMID: 33602509 DOI: 10.1016/j.jphs.2021.01.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023] Open
Abstract
2,6-Dimethoxy-1,4-benzoquinone (2,6-DMBQ) is the major bioactive compound found in fermented wheat germ extract. Although fermented wheat germ extract has been reported to show anti-proliferative and anti-metabolic effects in various cancers, the anticancer potential and molecular mechanisms exerted by 2,6-DMBQ have not been investigated in non-small cell lung cancer (NSCLC) cells. Here, we report that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibiting activation of AKT and p38 MAPK. 2,6-DMBQ significantly suppressed anchorage-dependent and independent cell growth. Additionally, 2,6-DMBQ induced G2 phase cell cycle arrest through inhibiting the expression and phosphorylation of cyclin B1 and CDC2, respectively. Furthermore, 2,6-DMBQ strongly suppressed NSCLC cell migration through induction of E-cadherin expression. To determine the molecular mechanism(s) exerted by 2,6-DMBQ upon NSCLC cell lines, various signaling kinases were screened; the results indicate that 2,6-DMBQ strongly inhibits the phosphorylation of AKT and p38 MAPK. Additionally, the growth kinetics of cells treated with an AKT or p38 MAPK inhibitor in combination with 2,6-DMBQ indicate that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibition of AKT and p38 MAPK. Taken together, our results suggest that 2,6-DMBQ is a potential anticancer reagent against NSCLC cells and could be useful for treating lung cancer patients.
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Affiliation(s)
- Xiaomeng Xie
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Xueyin Zu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Kyle Laster
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450008, China; The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, 450008, China; International Joint Research Center of Cancer Chemoprevention, Zhengzhou, China
| | - Dong Joon Kim
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450008, China.
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26
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Guo Y, Song J, Wang Y, Huang L, Sun L, Zhao J, Zhang S, Jing W, Ma J, Han C. Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review. Front Oncol 2020; 10:610923. [PMID: 33363040 PMCID: PMC7758444 DOI: 10.3389/fonc.2020.610923] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.
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Affiliation(s)
- Yijia Guo
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun Song
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yanru Wang
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Letian Huang
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Li Sun
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianzhu Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuling Zhang
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei Jing
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jietao Ma
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chengbo Han
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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27
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Torrealba N, Vera R, Fraile B, Martínez-Onsurbe P, Paniagua R, Royuela M. TGF-β/PI3K/AKT/mTOR/NF-kB pathway. Clinicopathological features in prostate cancer. Aging Male 2020; 23:801-811. [PMID: 30973040 DOI: 10.1080/13685538.2019.1597840] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Prostate cancer is one of the most common cancers in the male population. The objective of this investigation was to study the relationship of components of transforming growth factor-B (TGF-β)/phosphoinositide-3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-kB) transduction pathway with clinical-pathological markers. By immunohistochemical methods, we determined the expression of several factors [TGF-β, Transforming Growth Factor B Receptor I (TGFBRI), TGFBRII, PI3K, AKT-Ser, AKT-Thr, mTOR, p-mTOR, inhibitor kB kinase (IKK), pIKK, inhibitor kB (IkB), pIkB, NF-kBp50, and NF-kBp65]. To know their relationship with established classical markers (Preoperative serum prostate specific antigen, pathological tumor stage, clinical tumor stage, Gleason score, perineural invasion, node involvement, positive surgical margins, biochemical progression, and survival) and their importance in the prognosis of biochemical progression, Spearman test, survival analysis, Log-rang test, Kaplan-Meier curves, univariate and multivariate Cox proportional Hazard regression analyses were performed. Spearman analysis showed that there was at least one correlation between TGF-β, TGFBRI, PI3K, pAKT-Thr, p-mTOR, NF-kBp50, and classical markers. Cox multivariate analysis between the prognostic variables (pathological tumor stage, Gleason score, and node involvement) and inmunohistochemical parameters confirmed TGFBR1 and PI3K as a prognostic and independent marker of biochemical progression in prostate cancer. Our results suggest that TGFBR1 and PI3K could be used as useful biomarkers for early diagnosis and prognoses for biochemical recurrence in prostate cancer after radical prostatectomy.
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Affiliation(s)
- Norelia Torrealba
- Department of Biomedicine and Biotechnology, University of Alcalá, Madrid, Spain
| | - Raúl Vera
- Department of Biomedicine and Biotechnology, University of Alcalá, Madrid, Spain
| | - Benito Fraile
- Department of Biomedicine and Biotechnology, University of Alcalá, Madrid, Spain
| | | | - Ricardo Paniagua
- Department of Biomedicine and Biotechnology, University of Alcalá, Madrid, Spain
| | - Mar Royuela
- Department of Biomedicine and Biotechnology, University of Alcalá, Madrid, Spain
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28
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Li G, Ding K, Qiao Y, Zhang L, Zheng L, Pan T, Zhang L. Flavonoids Regulate Inflammation and Oxidative Stress in Cancer. Molecules 2020; 25:E5628. [PMID: 33265939 PMCID: PMC7729519 DOI: 10.3390/molecules25235628] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is the second leading cause of death globally. Millions of persons die due to cancer each year. In the last two decades, the anticancer effects of natural flavonoids have become a hot topic in many laboratories. Meanwhile, flavonoids, of which over 8000 molecules are known to date, are potential candidates for the discovery of anticancer drugs. The current review summarizes the major flavonoid classes of anticancer efficacy and discusses the potential anti-cancer mechanisms through inflammation and oxidative stress action, which were based on database and clinical studies within the past years. The results showed that flavonoids could regulate the inflammatory response and oxidative stress of tumor through some anti-inflammatory mechanisms such as NF-κB, so as to realize the anti-tumor effect.
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Affiliation(s)
| | | | | | | | | | | | - Lin Zhang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China; (G.L.); (K.D.); (Y.Q.); (L.Z.); (L.Z.); (T.P.)
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29
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Zheng X, Dong L, Zhao S, Li Q, Liu D, Zhu X, Ge X, Li R, Wang G. Propofol Affects Non-Small-Cell Lung Cancer Cell Biology By Regulating the miR-21/PTEN/AKT Pathway In Vitro and In Vivo. Anesth Analg 2020; 131:1270-1280. [PMID: 32925348 DOI: 10.1213/ane.0000000000004778] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Propofol is a common sedative-hypnotic drug traditionally used for inducing and maintaining general anesthesia. Recent studies have drawn attention to the nonanesthetic effects of propofol, but the potential mechanism by which propofol suppresses non-small-cell lung cancer (NSCLC) progression has not been fully elucidated. METHODS For the in vitro experiments, we used propofol (0, 2, 5, and 10 µg/mL) to treat A549 cells for 1, 4, and 12 hours and Cell Counting Kit-8 (CCK-8) to detect proliferation. Apoptosis was measured with flow cytometry. We also transfected A549 cells with an microribonucleic acid-21 (miR-21) mimic or negative control ribonucleic acid (RNA) duplex and phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) small interfering ribonucleic acid (siRNA) or negative control. PTEN, phosphorylated protein kinase B (pAKT), and protein kinase B (AKT) expression were detected using Western blotting, whereas miR-21 expression was examined by real-time polymerase chain reaction (RT-PCR). In vivo, nude mice were given injections of A549 cells to grow xenograft tumors; 8 days later, the mice were intraperitoneally injected with propofol (35 mg/kg) or soybean oil. Tumors were then collected from mice and analyzed by immunohistochemistry and Western blotting. RESULTS Propofol inhibited growth (1 hour, P = .001; 4 hours, P ≤ .0001; 12 hours, P = .0004) and miR-21 expression (P ≤ .0001) and induced apoptosis (1 hour, P = .0022; 4 hours, P = .0005; 12 hours, P ≤ .0001) in A549 cells in a time and concentration-dependent manner. MiR-21 mimic and PTEN siRNA transfection antagonized the suppressive effects of propofol on A549 cells by decreasing PTEN protein expression (mean differences [MD] [95% confidence interval {CI}], -0.51 [-0.86 to 0.16], P = .0058; MD [95% CI], 0.81 [0.07-1.55], P = .0349, respectively), resulting in an increase in pAKT levels (MD [95% CI] = -0.82 [-1.46 to -0.18], P = .0133) following propofol exposure. In vivo, propofol treatment reduced NSCLC tumor growth (MD [95% CI] = -109.47 [-167.03 to -51.91], P ≤ .0001) and promoted apoptosis (MD [95% CI] = 38.53 [11.69-65.36], P = .0093). CONCLUSIONS Our study indicated that propofol inhibited A549 cell growth, accelerated apoptosis via the miR-21/PTEN/AKT pathway in vitro, suppressed NSCLC tumor cell growth, and promoted apoptosis in vivo. Our findings provide new implications for propofol in cancer therapy and indicate that propofol is extremely advantageous in surgical treatment.
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Affiliation(s)
- Xiaoyu Zheng
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Linlin Dong
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, China
| | - Su Zhao
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Quanyi Li
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dandan Liu
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xidong Zhu
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaona Ge
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ruzhe Li
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guonian Wang
- From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China
- Department of Anesthesiology, Pain Research Institute of Heilongjiang Academy of Medical Sciences, Harbin, China
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30
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Apostolou A, Poreau B, Delrieu L, Thévenon J, Jouk PS, Lallemand G, Emadali A, Sartelet H. High Activation of the AKT Pathway in Human Multicystic Renal Dysplasia. Pathobiology 2020; 87:302-310. [PMID: 32927453 DOI: 10.1159/000509152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/04/2020] [Indexed: 11/19/2022] Open
Abstract
Multicystic renal dysplasia is a congenital cystic anomaly of the kidney caused by abnormal metanephric differentiation with immature tubules. It is surrounded by mesenchymal collars and islands of immature mesenchyma present between the cysts. The PI3K-AKT-mTOR signaling pathway is a key regulator involved in cell growth, proliferation, motility, survival, and apoptosis. Activation of the PI3K-AKT-mTOR pathway results in the survival and proliferation of tumor cells in many cancers. The aim of this study is to analyze the topographic expression of phospho-AKT, phospho-mTOR, and phospho-70S6K in renal development and in the multicystic dysplastic kidney (MCDK). A total of 17 fetal kidneys of development age from the first to the third trimester and 13 cases of pathological kidneys with MCDK were analyzed by immunohistochemistry in order to evaluate the expression of phospho-AKT (S473), phospho-mTOR, and phospho-70S6K. Phospho-AKT and phospho-mTOR were expressed early in renal development and in an identical manner for every structure derived from the ureteric bud, such as collecting ducts and urothelium. Phospho-p70S6K was expressed early in the urothelium and in glomerular mesangial cells. Later, their expressions differed according to the needs of cell proliferation and differentiation over time by becoming more selective. In MCDK, phospho-AKT, phospho-mTOR, and phospho-70S6K have the same profile: a high cytoplasmic expression in cystic epithelium, loose mesenchyma, and primitive tubes. This study demonstrates the essential and specific role of the PI3K-AKT-mTOR pathway in the formation of cysts in multicystic renal dysplasia.
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Affiliation(s)
- Alexia Apostolou
- Department of Pathology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.,Universite Grenoble Alpes, Grenoble, France
| | - Brice Poreau
- Department of Genetics, Couple Children's Hospital, Grenoble, France.,Universite Grenoble Alpes, Grenoble, France
| | - Loris Delrieu
- Translational Epigenetics,Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
| | - Julien Thévenon
- Department of Genetics, Couple Children's Hospital, Grenoble, France.,Universite Grenoble Alpes, Grenoble, France
| | - Pierre-Simon Jouk
- Department of Genetics, Couple Children's Hospital, Grenoble, France.,Universite Grenoble Alpes, Grenoble, France
| | - Guillaume Lallemand
- Department of Genetics, Couple Children's Hospital, Grenoble, France.,Universite Grenoble Alpes, Grenoble, France
| | - Anouk Emadali
- Translational Epigenetics,Institute for Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.,Pôle Recherche, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Herve Sartelet
- Department of Pathology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France, .,Universite Grenoble Alpes, Grenoble, France,
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31
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Hu ZY, Huang WY, Zhang L, Huang B, Chen SC, Li XL. Expression of AKT and p-AKT protein in lung adenocarcinoma and its correlation with PD-L1 protein and prognosis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1172. [PMID: 33241021 PMCID: PMC7576079 DOI: 10.21037/atm-20-5865] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background The PI3K/AKT/mTOR signaling pathway were significantly associated with EGFR mutation in lung adenocarcinoma (LUAD), but its correlation with PD-L1 protein and prognosis are not clear. The aim of this study was to evaluate the expression of AKT and phosphorylated AKT (p-AKT) in LUAD and its correlation with programmed death ligand-1 (PD-L1); and to analyze the factors affecting LUAD prognosis. Methods The expression of AKT, p-AKT, and PD-L1 was examined using immunohistochemistry in LUAD tissues from 110 patients who underwent surgical treatment. Results AKT protein expression was examined in 64.5% (71/110) of the LUAD samples, and p-AKT protein expression was examined in 44.5% (49/110) of the LUAD samples. The positive rate of PD-L1 at TC1/2/3 was 38.2% (42/110). AKT and p-AKT expression was significantly associated with epidermal growth factor receptor (EGFR) mutation (P=0.016, P=0.014 respectively). Pearson's correlation analysis indicated a negative correlation of p-AKT with PD-L1 protein (P=0.022). Out of the 62 patients with EGFR mutation, the expression of PD-L1 was negatively correlated with that of p-AKT protein (P=0.032). The expressions of AKT and p-AKT were not associated with prognosis. Multivariate analysis showed that tumor-node-metastasis (TNM) stage (P=0.013) and differentiation (P=0.046) were independent prognostic factors for overall survival. Conclusions PI3K/AKT/mTOR in the downstream pathway of EGFR may negatively regulate the expression of PD-L1, which may partly explain why patients with EGFR mutation respond poorly to PD-1/PD-L1 inhibitors.
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Affiliation(s)
- Zhi-Ying Hu
- Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.,Department of Respiratory and Critical Care Medicine, Dalian Third People's Hospital, Dalian, China
| | - Wan-Yi Huang
- Department of aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Lei Zhang
- Department of Oncology, Shenyang Fifth People Hospital, Shenyang, China
| | - Bo Huang
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Shu-Chen Chen
- Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Xiao-Ling Li
- Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
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32
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Assessment of Serum Tumor Markers for Predicting Ocular Metastasis in Lung Adenocarcinoma: A Retrospective Study. DISEASE MARKERS 2020; 2020:2102158. [PMID: 32685054 PMCID: PMC7334773 DOI: 10.1155/2020/2102158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 02/01/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022]
Abstract
The purpose of this study was to detect clinical variations between lung adenocarcinoma patients with and without ocular metastasis (OM) to identify risk factors for OM and assess the diagnostic values. We included 1153 patients with lung adenocarcinoma in this study. Independent t-tests and chi-square tests were used to compare patients' clinical characteristics. Statistically significant parameters were analyzed by binary logistic regression to detect risk factors of OM. The results showed that the OM group had increased alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21-1), carbohydrate antigen- (CA-) 125, CA-153, and total prostate-specific antigen (TPSA) compared with the NOM group. CYFRA21-1 is the most useful biomarker for detecting OM in this population.
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33
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Yu W, Chen PB, Chen FC, Ding SL, Pan XY. MicroRNA-744 promotes proliferation of osteosarcoma cells by targeting PTEN. Mol Med Rep 2020; 21:2276-2282. [PMID: 32186762 DOI: 10.3892/mmr.2020.11030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 02/25/2020] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are non-coding RNAs that regulate protein synthesis by targeting mRNAs for translational repression or degradation. Previous studies have reported that aberrant expression of miR‑744 may be involved in human osteosarcoma; however, the underlying mechanisms remain elusive. In the present study, the expression levels of miR‑744 and its downstream signals were determined by reverse transcription‑quantitative PCR and western blotting. Cell proliferation was assessed using the bromodeoxyuridine assay, and the target of miR‑744 was investigated using a dual‑luciferase activity assay. The present study identified a significant upregulation of miR‑744 in osteosarcoma tissues compared with adjacent non‑tumor tissues. Furthermore, it was demonstrated that ectopic overexpression of miR‑744 induced by a miR‑744 precursor significantly enhanced proliferation of the osteosarcoma cell line MG63, whereas opposite results were observed following suppression of miR‑744 with its inhibitor. Moreover, as a unique anti‑oncogene, PTEN was identified as a direct target of miR‑744. It was confirmed that miR‑744 downregulated PTEN expression in MG63 cells by targeting the PTEN 3'untranslated region, and that the downstream AKT signal was also regulated by miR‑744. Collectively, the present results suggested that miR‑744 promoted proliferation of human osteosarcoma cells by directly regulating the PTEN/AKT signaling pathway.
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Affiliation(s)
- Wei Yu
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Peng-Bo Chen
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
| | - Fan-Cheng Chen
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200433, P.R. China
| | - Sheng-Long Ding
- Department of Orthopedics, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, P.R. China
| | - Xiao-Yun Pan
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Chang L, Fang S, Gu W. The Molecular Mechanism of Metabolic Remodeling in Lung Cancer. J Cancer 2020; 11:1403-1411. [PMID: 32047547 PMCID: PMC6995370 DOI: 10.7150/jca.31406] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 10/23/2019] [Indexed: 12/11/2022] Open
Abstract
Metabolic remodeling is a key phenomenon in the occurrence and development of tumors. It not only offers materials and energy for the survival and proliferation of tumor cells, but also protects tumor cells so that they may survive, proliferate and transfer in the harsh microenvironment. This paper attempts to reveal the role of abnormal metabolism in the development of lung cancer by considering the processes of glycolysis and lipid metabolism, Identification of the molecules that are specifically used in the processes of glycolysis and lipid metabolism, and their underlying molecular mechanisms, is of great clinical and theoretical significance. We will focus on the recent progress in elucidating the molecular mechanism of metabolic remodeling in lung cancer.
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Affiliation(s)
| | | | - Wei Gu
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University. No. 68 Changle Road, Qinhuai District, Nanjing 210001,People's Republic of China
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LIU C, SUN E, MENG W, SUN G. Protective effect of crocetin from Crocus sativus L. on myocardial ischemia-reperfusion injury in rats. FOOD SCIENCE AND TECHNOLOGY 2019. [DOI: 10.1590/fst.28918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Ma X, Liang AL, Liu YJ. Research progress on the relationship between lung cancer drug-resistance and microRNAs. J Cancer 2019; 10:6865-6875. [PMID: 31839821 PMCID: PMC6909942 DOI: 10.7150/jca.31952] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 09/13/2019] [Indexed: 02/07/2023] Open
Abstract
Lung cancer, a malignant tumor with the highest death rate of cancer, seriously endangers human health. And its pathogenesis and mechanism of drug resistance has been partially clarified, especially for the signal pathway of epidermal growth factor receptor (EGFR). The targeting therapy of EGFR signaling pathway in non-small cell lung cancer (NSCLC) has achieved a certain effect, but the two mutation of EGFR and other mechanisms of lung cancer resistance still greatly reduce the therapeutic effect of chemotherapy on it. MicroRNA is an endogenous non coding RNA, which has a regulatory function after transcriptional level. Recent studies on the mechanism of lung cancer resistance have found that a variety of microRNAs are related to the mechanism of lung cancer drug-resistance. They can regulate lung cancer resistance by participating in signal pathways, drug resistance genes and cell apoptosis, thus affecting the sensitivity of cancer cells to drugs. Therefore, microRNAs can be used as a specific target for the treatment of lung cancer and plays a vital role in the early diagnosis, prognosis and treatment of lung cancer. This article reviews the mechanisms of lung cancer resistance and its relationship with microRNAs.
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Affiliation(s)
| | | | - Yong-Jun Liu
- Medical Molecular Diagnostics Key Laboratory of Guangdong & Departments of Biochemistry and Molecular Biology & Departments of Clinical Biochemistry, Guangdong Medical University, 523808, Dongguan, Guangdong, P.R. China
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Gkountakos A, Sartori G, Falcone I, Piro G, Ciuffreda L, Carbone C, Tortora G, Scarpa A, Bria E, Milella M, Rosell R, Corbo V, Pilotto S. PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around. Cancers (Basel) 2019; 11:cancers11081141. [PMID: 31404976 PMCID: PMC6721522 DOI: 10.3390/cancers11081141] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/27/2019] [Accepted: 07/29/2019] [Indexed: 12/15/2022] Open
Abstract
Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of its levels increases cancer susceptibility. While the most validated anti-oncogenic duty of PTEN is the negative regulation of the PI3K/mTOR/Akt oncogenic signaling pathway, further tumor suppressor functions, such as chromosomal integrity and DNA repair have been reported. PTEN protein loss is a frequent event in lung cancer, but genetic alterations are not equally detected. It has been demonstrated that its expression is regulated at multiple genetic and epigenetic levels and deeper delineation of these mechanisms might provide fertile ground for upgrading lung cancer therapeutics. Today, PTEN expression is usually determined by immunohistochemistry and low protein levels have been associated with decreased survival in lung cancer. Moreover, available data involve PTEN mutations and loss of activity with resistance to targeted treatments and immunotherapy. This review discusses the current knowledge about PTEN status in lung cancer, highlighting the prevalence of its alterations in the disease, the regulatory mechanisms and the implications of PTEN on available treatment options.
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Affiliation(s)
- Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Giulia Sartori
- Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, 37134 Verona, Italy
| | - Italia Falcone
- Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Geny Piro
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy
| | - Ludovica Ciuffreda
- SAFU Laboratory, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Carmine Carbone
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
- Center for Applied Research on Cancer (ARC-NET), University of Verona, 37134 Verona, Italy
| | - Emilio Bria
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Medical Oncology, Università Cattolica Del Sacro Cuore, 00168 Rome, Italy
| | - Michele Milella
- Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, 37134 Verona, Italy
| | - Rafael Rosell
- Germans Trias i Pujol, Health Sciences Institute and Hospital, Campus Can Ruti, 08916 Badalona, Spain
| | - Vincenzo Corbo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.
- Center for Applied Research on Cancer (ARC-NET), University of Verona, 37134 Verona, Italy.
| | - Sara Pilotto
- Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, 37134 Verona, Italy.
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Shen J, Xu J, Chen B, Ma D, Chen Z, Li JC, Zhu C. Elevated integrin α6 expression is involved in the occurrence and development of lung adenocarcinoma, and predicts a poor prognosis: a study based on immunohistochemical analysis and bioinformatics. J Cancer Res Clin Oncol 2019; 145:1681-1693. [PMID: 31175464 DOI: 10.1007/s00432-019-02907-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 03/22/2019] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To study integrin α6 expression in lung adenocarcinoma tissue through comparison with matching adjacent non-cancerous tissues as well as elucidating the correlation between integrin α6 expression with the clinical parameters of lung adenocarcinoma. We also explore the signal pathways associated with integrin α6 up-regulation. METHODS The clinical data, cancer tissues, and adjacent non-cancerous tissues of 30 patients diagnosed with lung adenocarcinoma were collected from Taizhou Hospital in Zhejiang Province, China, in 2010. The protein levels of integrin α6 were determined by immunohistochemistry methods. mRNA data of 85 lung adenocarcinoma tissues and 14 normal tissues as well as clinical results were collected from GEO30219. We also collected mRNA data of 533 lung adenocarcinoma tissues and 59 normal tissues as well as the clinical results of 522 patients with lung adenocarcinoma from the Cancer Genome Atlas (TCGA) database. The differences in protein and mRNA levels in cancer tissues and non-cancerous tissues were analyzed, and we subsequently investigated the association between integrin α6 expression and key parameters indicating lung adenocarcinoma progression and overall survival rate. Additionally, the possible pathways involved in the up-regulation of integrin α6 were analyzed by GSEA. RESULTS The protein levels of integrin α6 in lung adenocarcinoma tissues were significantly higher than those in adjacent tissues (p < 0.01), and were positively correlated with the grade and T stage of lung adenocarcinoma (p < 0.05). Patients with low integrin α6 protein levels had higher survival rates (p < 0.05). The analysis of gene chip data from the TCGA database also showed that the integrin α6 mRNA level was significantly correlated with T stage (p < 0.05), overall survival (OS) rate (p < 0.01), and disease-free survival (DFS) rate (p = 0.005). GSEA gene enrichment analysis identified a series of pathways that may be associated with integrin α6 up-regulation, including the AGR, PYK2, ECM, and PTEN pathways. CONCLUSION Integrin α6 plays an important role in the occurrence and progression of lung adenocarcinoma and may act as a prognostic predictor of lung adenocarcinoma in patients. Based on the results of the present study, integrin α6 may be a potential target gene for the treatment of lung adenocarcinoma.
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Affiliation(s)
- Jianfei Shen
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Taizhou, 317000, China
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China
- Institute of Cell Biology, Zhejiang University, Hangzhou, 310058, China
| | - Jianfeng Xu
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China
| | - Baofu Chen
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China
| | - Dehua Ma
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China
| | - Zixuan Chen
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China
| | - Ji-Cheng Li
- Institute of Cell Biology, Zhejiang University, Hangzhou, 310058, China.
| | - Chengchu Zhu
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Taizhou, 317000, China.
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, 317000, China.
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Weng MC, Li MH, Chung JG, Liu YC, Wu JY, Hsu FT, Wang HE. Apoptosis induction and AKT/NF-κB inactivation are associated with regroafenib-inhibited tumor progression in non-small cell lung cancer in vitro and in vivo. Biomed Pharmacother 2019; 116:109032. [PMID: 31163381 DOI: 10.1016/j.biopha.2019.109032] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 01/11/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is a malignant lung cancer type with poor prognosis. NF-κB, the oncogenic transcription factor, has been recognized as an important mediator in progression of NSCLC. Regorafenib, a multikinase inhibitor, was demonstrated to inhibit tumor progression through suppression of ERK/NF-κB signaling in hepatocellular carcinoma cells in vitro and in vivo. However, whether regorafenib inhibit progression of NSCLC is ambiguous. Thus, the major purpose of present study was to evaluate anticancer efficacy and underlying mechanism of regorafenib on tumor progression in NSCLC in vitro and in vivo. CL-1-5-F4 cells were treated with regorafenib, NF-κB (QNZ) or AKT (LY294002) inhibitor for 24 or 48 h. Then, we performed cell viability assay, NF-κB reporter gene assay, transwell invasion assay and apoptosis related flow cytometry assay on cellular level to verify anti-cancer effect and mechanism of regorafenib. CL-1-5-F4 bearing animal model was treated with vehicle or regorafenib for 28 days. The therapeutic efficacy and mechanism of regorafenib in CL-1-5-F4 bearing animal model were investigated by tumor size evaluation, whole body computer tomography (CT) scan, Haemotoxylin and Eosin (H&E) stain and immunohistochemistry (IHC) stain. Our results demonstrated regorafenib significantly inhibited tumor growth and induced apoptosis through extrinsic/intrinsic pathways in NSCLC in vitro and in vivo. Furthermore, we also found the suppression of AKT/NF-κB signaling was required for regorafenib inhibited expression of progression-related and invasion-related proteins. Our finding indicated apoptosis induction and suppression of AKT/NF-κB signaling were associated with regorafenib-inhibited progression of NSCLC in vitro and in vivo.
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Affiliation(s)
- Mao-Chi Weng
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan; Isotope Application Division, Institute of Nuclear Energy Research, Atomic Energy Council, Taiwan
| | - Ming-Hsin Li
- Isotope Application Division, Institute of Nuclear Energy Research, Atomic Energy Council, Taiwan
| | - Jing Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Yu-Chang Liu
- Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan; Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan; Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Jeng-Yuan Wu
- Department of Thoracic Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Fei-Ting Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
| | - Hsin-Ell Wang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan.
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Jiang M, Zhou LY, Xu N, An Q. Hydroxysafflor yellow A inhibited lipopolysaccharide-induced non-small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways. Thorac Cancer 2019; 10:1319-1333. [PMID: 31055884 PMCID: PMC6558494 DOI: 10.1111/1759-7714.13019] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/27/2019] [Accepted: 01/28/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Chronic inflammation plays a significant role in the occurrence and development of non-small cell lung cancer (NSCLC). Hydroxysafflor yellow A (HSYA), a chemical compound of the yellow color pigments extracted from the safflower, has been widely used in clinical treatment with positive antioxidation, anti-inflammation, and antitumor effects. However, the role and underlying mechanisms of HYSA on development and progress in inflammation-mediated NSCLC are unknown. METHODS Cell counting kit-8, colony formation, EdU, cell apoptosis, wound healing, Transwell migration and invasion, and enzyme-linked immunosorbent assays; flow cytometry; and Western blotting were conducted using human NSCLC cell lines A549 and H1299. RESULTS Lipopolysaccharide (LPS) significantly promoted the proliferation and enhanced colony formation of A549 and H1299 cells, while HYSA notably reversed the effects of LPS. HYSA induced apoptosis of LPS-mediated A549 and H1299 cells in a dose dependent manner; and remarkably suppressed migration, invasion, and epithelial-mesenchymal transition (EMT), significantly regulated production of LPS-induced inflammation cytokines, and downregulated protein expression of PI3K/Akt/mTOR and ERK/MAPK signaling pathways in LPS-induced A549 and H1299 cells. Furthermore, PI3K (LY294002) and ERK (SCH772984) inhibitors remarkably inhibited proliferation, migration, invasion, and EMT, and induced apoptosis in LPS-mediated A549 and H1299 cells. These effects were even more obvious in the presence of HYSA and LY294002 or SCH772984 compared to those of either agent alone. CONCLUSION HYSA suppressed LPS-mediated proliferation, migration, invasion, and EMT in A549 and H1299 cells by inhibiting the PI3K/Akt/mTOR and ERK/MAPK signaling pathways, indicating that HYSA may be a potential candidate to treat inflammation-mediated NSCLC.
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Affiliation(s)
- Ming Jiang
- Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Li-Yang Zhou
- Department of Respiratory Medicine, Huai'an Second People's Hospital of Jiangsu, Huaian, China
| | - Nan Xu
- Department of Traditional Chinese Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Qing An
- Department of Traditional Chinese Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Yang S, Sui J, Liu T, Wu W, Xu S, Yin L, Pu Y, Zhang X, Zhang Y, Shen B, Liang G. Expression of miR-486-5p and its significance in lung squamous cell carcinoma. J Cell Biochem 2019; 120:13912-13923. [PMID: 30963622 DOI: 10.1002/jcb.28665] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/21/2019] [Accepted: 02/28/2019] [Indexed: 12/14/2022]
Abstract
Lung squamous cell carcinoma (LUSC) is one of the main histological types of lung cancer with high mortality. The role of microRNA-486-5p in LUSC remains unclear. In the current study, the aim was to explore miR-486-5p expression and its role in LUSC. The miR-486-5p expression was significantly low-expressed in patients with LUSC from The Cancer Genome Atlas database, which was further confirmed in the Gene Expression Omnibus database, patients' tissues, different cell lines by quantitative real-time polymerase chain reaction, and the high-throughput gene sequencing data of lung tissues of mice after a long-term B(a)P exposure. The meta-analysis was performed to evaluate the expression and diagnosis power of miR-486-5p (standard mean difference = -2.25; 95% confidence interval: -3.47 to -1.03; P = 0.0003; area under curve = 0.9082). Functional enrichment analysis revealed the potential function of miR-486-5p in LUSC using gene set enrichment analysis and clusterProfiler package in R software. At last, the hub genes (PTEN, TEK, PIK3R1, PPM1B, SMAD2, and SPTA1) of miR-486-5p were verified. In conclusion, miR-486-5p may be a LUSC antioncogene, playing an important role to serve as a biomarker in LUSC.
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Affiliation(s)
- Sheng Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Jing Sui
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Tong Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Wenjuan Wu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Siyi Xu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Lihong Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
| | - Xiaomei Zhang
- Department of Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, P.R. China
| | - Yan Zhang
- Department of Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, P.R. China
| | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, P.R. China
| | - Geyu Liang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, P.R. China
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Perumal E, So Youn K, Sun S, Seung-Hyun J, Suji M, Jieying L, Yeun-Jun C. PTEN inactivation induces epithelial-mesenchymal transition and metastasis by intranuclear translocation of β-catenin and snail/slug in non-small cell lung carcinoma cells. Lung Cancer 2019; 130:25-34. [PMID: 30885348 DOI: 10.1016/j.lungcan.2019.01.013] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/26/2018] [Accepted: 01/27/2019] [Indexed: 12/11/2022]
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Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, Jiang B, Feng J, Li J, Gu Y. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep 2018; 19:783-791. [PMID: 30535469 PMCID: PMC6323245 DOI: 10.3892/mmr.2018.9713] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 09/17/2018] [Indexed: 12/13/2022] Open
Abstract
The purpose of this review is to summarize the research progress of PI3K/Akt signaling pathway in erythropoiesis and glycolysis. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is activated by numerous genes and leads to protein kinase B (Akt) binding to the cell membrane, with the help of phosphoinositide-dependent kinase, in the PI3K/Akt signal transduction pathway. Threonine and serine phosphorylation contribute to Akt translocation from the cytoplasm to the nucleus and further mediates enzymatic biological effects, including those involved in cell proliferation, apoptosis inhibition, cell migration, vesicle transport and cell cancerous transformation. As a key downstream protein of the PI3K/Akt signaling pathway, hypoxia-inducible factor (HIF)-1 is closely associated with the concentration of oxygen in the environment. Maintaining stable levels of HIF-1 protein is critical under normoxic conditions; however, HIF-1 levels quickly increase under hypoxic conditions. HIF-1α is involved in the acute hypoxic response associated with erythropoietin, whereas HIF-2α is associated with the response to chronic hypoxia. Furthermore, PI3K/Akt can reduce the synthesis of glycogen and increase glycolysis. Inhibition of glycogen synthase kinase 3β activity by phosphorylation of its N-terminal serine increases accumulation of cyclin D1, which promotes the cell cycle and improves cell proliferation through the PI3K/Akt signaling pathway. The PI3K/Akt signaling pathway is closely associated with a variety of enzymatic biological effects and glucose metabolism.
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Affiliation(s)
- Youbang Xie
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Xuefeng Shi
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Kuo Sheng
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Guoxiong Han
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Wenqian Li
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Qiangqiang Zhao
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Baili Jiang
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Jianming Feng
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Jianping Li
- Department of Hematology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Yuhai Gu
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
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Xie XP, Xie YF, Liu YT, Wang HQ. Adaptively capturing the heterogeneity of expression for cancer biomarker identification. BMC Bioinformatics 2018; 19:401. [PMID: 30390627 PMCID: PMC6215657 DOI: 10.1186/s12859-018-2437-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 10/15/2018] [Indexed: 11/25/2022] Open
Abstract
Background Identifying cancer biomarkers from transcriptomics data is of importance to cancer research. However, transcriptomics data are often complex and heterogeneous, which complicates the identification of cancer biomarkers in practice. Currently, the heterogeneity still remains a challenge for detecting subtle but consistent changes of gene expression in cancer cells. Results In this paper, we propose to adaptively capture the heterogeneity of expression across samples in a gene regulation space instead of in a gene expression space. Specifically, we transform gene expression profiles into gene regulation profiles and mathematically formulate gene regulation probabilities (GRPs)-based statistics for characterizing differential expression of genes between tumor and normal tissues. Finally, an unbiased estimator (aGRP) of GRPs is devised that can interrogate and adaptively capture the heterogeneity of gene expression. We also derived an asymptotical significance analysis procedure for the new statistic. Since no parameter needs to be preset, aGRP is easy and friendly to use for researchers without computer programming background. We evaluated the proposed method on both simulated data and real-world data and compared with previous methods. Experimental results demonstrated the superior performance of the proposed method in exploring the heterogeneity of expression for capturing subtle but consistent alterations of gene expression in cancer. Conclusions Expression heterogeneity largely influences the performance of cancer biomarker identification from transcriptomics data. Models are needed that efficiently deal with the expression heterogeneity. The proposed method can be a standalone tool due to its capacity of adaptively capturing the sample heterogeneity and the simplicity in use. Software availability The source code of aGRP can be downloaded from https://github.com/hqwang126/aGRP. Electronic supplementary material The online version of this article (10.1186/s12859-018-2437-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xin-Ping Xie
- School of Mathematics and Physics, Anhui Jianzhu University, Hefei, 230022, Anhui, China
| | - Yu-Feng Xie
- School of Mathematics and Physics, Anhui Jianzhu University, Hefei, 230022, Anhui, China.,Institute of Intelligent Machines, Hefei Institutes of Physical Science, CAS, 350 Shushanhu Road, P.O.Box 1130, Hefei, 230031, Anhui, China.,Present Address: School of Electronics and Information, Northwestern Polytechnical University, Xi'an, 710100, China
| | - Yi-Tong Liu
- School of Mathematics and Physics, Anhui Jianzhu University, Hefei, 230022, Anhui, China.,Institute of Intelligent Machines, Hefei Institutes of Physical Science, CAS, 350 Shushanhu Road, P.O.Box 1130, Hefei, 230031, Anhui, China
| | - Hong-Qiang Wang
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, CAS, 350 Shushanhu Road, P.O.Box 1130, Hefei, 230031, Anhui, China.
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45
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Maiuthed A, Bhummaphan N, Luanpitpong S, Mutirangura A, Aporntewan C, Meeprasert A, Rungrotmongkol T, Rojanasakul Y, Chanvorachote P. Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation. J Biol Chem 2018; 293:13534-13552. [PMID: 29986880 DOI: 10.1074/jbc.ra117.000287] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 06/19/2018] [Indexed: 01/11/2023] Open
Abstract
Cancer stem cells (CSCs) are unique populations of cells that can self-renew and generate different cancer cell lineages. Although CSCs are believed to be a promising target for novel therapies, the specific mechanisms by which these putative therapeutics could intervene are less clear. Nitric oxide (NO) is a biological mediator frequently up-regulated in tumors and has been linked to cancer aggressiveness. Here, we search for targets of NO that could explain its activity. We find that it directly affects the stability and function of octamer-binding transcription factor 4 (Oct4), known to drive the stemness of lung cancer cells. We demonstrated that NO promotes the CSC-regulatory activity of Oct4 through a mechanism that involves complex formation between Oct4 and the scaffolding protein caveolin-1 (Cav-1). In the absence of NO, Oct4 forms a molecular complex with Cav-1, which promotes the ubiquitin-mediated proteasomal degradation of Oct4. NO promotes Akt-dependent phosphorylation of Cav-1 at tyrosine 14, disrupting the Cav-1:Oct4 complex. Site-directed mutagenesis and computational modeling studies revealed that the hydroxyl moiety at tyrosine 14 of Cav-1 is crucial for its interaction with Oct4. Both removal of the hydroxyl via mutation to phenylalanine and phosphorylation lead to an increase in binding free energy (ΔGbind) between Oct4 and Cav-1, destabilizing the complex. Together, these results unveiled a novel mechanism of CSC regulation through NO-mediated stabilization of Oct4, a key stem cell transcription factor, and point to new opportunities to design CSC-related therapeutics.
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Affiliation(s)
- Arnatchai Maiuthed
- From the Department of Pharmacology and Physiology.,Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences
| | - Narumol Bhummaphan
- Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences.,the Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sudjit Luanpitpong
- the Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700 Thailand, and
| | - Apiwat Mutirangura
- the Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, and
| | | | - Arthitaya Meeprasert
- Structural and Computational Biology Research Group, and Department of Biochemistry, Faculty of Science
| | - Thanyada Rungrotmongkol
- Structural and Computational Biology Research Group, and Department of Biochemistry, Faculty of Science.,Ph.D. Program in Bioinformatics and Computational Biology
| | - Yon Rojanasakul
- WVU Cancer Institute, West Virginia University, Morgantown, West Virginia 26506
| | - Pithi Chanvorachote
- From the Department of Pharmacology and Physiology, .,Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences
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46
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Morgillo F, Dallio M, Della Corte CM, Gravina AG, Viscardi G, Loguercio C, Ciardiello F, Federico A. Carcinogenesis as a Result of Multiple Inflammatory and Oxidative Hits: a Comprehensive Review from Tumor Microenvironment to Gut Microbiota. Neoplasia 2018; 20:721-733. [PMID: 29859426 PMCID: PMC6014569 DOI: 10.1016/j.neo.2018.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/30/2018] [Accepted: 05/01/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Floriana Morgillo
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy.
| | - Marcello Dallio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carminia Maria Della Corte
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Antonietta Gerarda Gravina
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Viscardi
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Carmelina Loguercio
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Federico
- Gastroenterologia, Dipartimento di Internistica Clinica e Sperimentale "F.Magrassi", Università della Campania "Luigi Vanvitelli", Naples, Italy
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47
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Malaney P, Palumbo E, Semidey-Hurtado J, Hardee J, Stanford K, Kathiriya JJ, Patel D, Tian Z, Allen-Gipson D, Davé V. PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer. Cell Cycle 2018; 17:947-962. [PMID: 29108454 PMCID: PMC6103743 DOI: 10.1080/15384101.2017.1388970] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 09/28/2017] [Accepted: 10/02/2017] [Indexed: 12/13/2022] Open
Abstract
PTEN phosphorylation at its C-terminal (C-tail) serine/threonine cluster negatively regulates its tumor suppressor function. However, the consequence of such inhibition and its downstream effects in driving lung cancer remain unexplored. Herein, we ascertain the molecular mechanisms by which phosphorylation compromises PTEN function, contributing to lung cancer. Replacement of the serine/threonine residues with alanine generated PTEN-4A, a phosphorylation-deficient PTEN mutant, which suppressed lung cancer cell proliferation and migration. PTEN-4A preferentially localized to the nucleus where it suppressed E2F1-mediated transcription of cell cycle genes. PTEN-4A physically interacted with the transcription factor E2F1 and associated with chromatin at gene promoters with E2F1 DNA-binding sites, a likely mechanism for its transcriptional suppression function. Deletion analysis revealed that the C2 domain of PTEN was indispensable for suppression of E2F1-mediated transcription. Further, we uncovered cancer-associated C2 domain mutant proteins that had lost their ability to suppress E2F1-mediated transcription, supporting the concept that these mutations are oncogenic in patients. Consistent with these findings, we observed increased PTEN phosphorylation and reduced nuclear PTEN levels in lung cancer patient samples establishing phosphorylation as a bona fide inactivation mechanism for PTEN in lung cancer. Thus, use of small molecule inhibitors that hinder PTEN phosphorylation is a plausible approach to activate PTEN function in the treatment of lung cancer. Abbreviations AKT V-Akt Murine Thymoma Viral Oncogene CA Cancer adjacent CDK1 Cyclin dependent kinase 1 CENPC-C Centromere Protein C ChIP Chromatin Immunoprecipitation co-IP Co-immunoprecipitation COSMIC Catalog of Somatic Mutations In Cancer CREB cAMP Responsive Element Binding Protein C-tail Carboxy terminal tail E2F1 E2F Transcription Factor 1 ECIS Electric Cell-substrate Impedance Sensing EGFR Epidermal Growth Factor Receptor GSI Gamma Secretase Inhibitor HDAC1 Histone Deacetylase 1 HP1 Heterochromatin protein 1 KAP1/TRIM28 KRAB-Associated Protein 1/Tripartite Motif Containing 28 MAF1 Repressor of RNA polymerase III transcription MAF1 homolog MCM2 Minichromosome Maintenance Complex Component 2 miRNA micro RNA MTF1 Metal-Regulatory Transcription Factor 1 PARP Poly(ADP-Ribose) Polymerase PD-1 Programmed Cell Death 1 PD-L1 Programmed Cell Death 1 Ligand 1 PI3K Phosphatidylinositol-4,5-Bisphosphate 3-Kinase PLK Polo-like Kinase pPTEN Phosphorylated PTEN PTEN Phosphatase and Tensin Homolog deleted on chromosome ten PTM Post Translational Modification Rad51 RAD51 Recombinase Rad52 RAD52 Recombinase RPA1 Replication protein A SILAC Stable Isotope Labeling with Amino Acids in Cell Culture SRF Serum Response Factor TKI Tyrosine Kinase inhbitors TMA Tissue Microarray TOP2A DNA Topoisomerase 2A.
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Affiliation(s)
- Prerna Malaney
- Department of Pathology and Cell Biology, Morsani College of Medicine
| | - Emily Palumbo
- Department of Pathology and Cell Biology, Morsani College of Medicine
| | | | - Jamaal Hardee
- Department of Pathology and Cell Biology, Morsani College of Medicine
| | | | | | - Deepal Patel
- Department of Pathology and Cell Biology, Morsani College of Medicine
| | - Zhi Tian
- College of Pharmacy, University of South Florida, Tampa, FL 33612, United States
| | - Diane Allen-Gipson
- College of Pharmacy, University of South Florida, Tampa, FL 33612, United States
| | - Vrushank Davé
- Department of Pathology and Cell Biology, Morsani College of Medicine
- Lung Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States
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48
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Liu Z, Wu Y, Tao Z, Ma L. E3 ubiquitin ligase Hakai regulates cell growth and invasion, and increases the chemosensitivity to cisplatin in non‑small‑cell lung cancer cells. Int J Mol Med 2018; 42:1145-1151. [PMID: 29786107 DOI: 10.3892/ijmm.2018.3683] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 04/26/2018] [Indexed: 11/06/2022] Open
Abstract
Hakai was originally identified as an E3 ubiquitin ligase of the E‑cadherin complex implicated in cell adhesion and invasion. Recently, emerging evidence has strongly suggested that Hakai serves a pivotal role in the tumorigenesis of certain tumors. However, the role of Hakai in non‑small‑cell lung cancer (NSCLC) and its underlying molecular mechanism have not been clarified. In the present study, it was observed that Hakai was highly expressed in NSCLC cell lines compared with human normal bronchial epithelial cells, and transfection with Hakai small interfering RNA significantly inhibited the growth of A549 and NCI‑H460 NSCLC cells. In addition, the inhibition of Hakai suppressed NSCLC cell migration and invasion through upregulation of E‑cadherin and downregulation of N‑cadherin. Notably, it was also revealed that knockdown of Hakai led to a decrease in the expression of phosphorylated AKT (Ser473), and a significant enhancement of chemosensitivity to cisplatin was observed following Hakai suppression. In conclusion, the present study demonstrated for the first time that knockdown of Hakai inhibited the proliferation, migration and invasion of NSCLC cells, and sensitized NSCLC cells to cisplatin. Thus, Hakai may serve as a potential therapeutic target for the treatment of NSCLC.
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Affiliation(s)
- Zi Liu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui 243002, P.R. China
| | - Yuqing Wu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui 243002, P.R. China
| | - Zijian Tao
- Department of Pathology, Ma'anshan Municipal People's Hospital, Ma'anshan, Anhui 243000, P.R. China
| | - Liang Ma
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui 243002, P.R. China
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49
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Huang L, Liu J, Zhang XO, Sibley K, Najjar SM, Lee MM, Wu Q. Inhibition of protein arginine methyltransferase 5 enhances hepatic mitochondrial biogenesis. J Biol Chem 2018; 293:10884-10894. [PMID: 29773653 DOI: 10.1074/jbc.ra118.002377] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/01/2018] [Indexed: 11/06/2022] Open
Abstract
Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat-induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral short hairpin RNA-mediated reduction of PRMT5 significantly decreased phosphatidylinositol 3-kinase/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation but boosted the expression of peroxisome proliferator-activated receptor α (PPARα) and PGC-1α with a concomitant increase in mitochondrial biogenesis. Moreover, by overexpressing an exogenous WT or enzyme-dead mutant PRMT5 or by inhibiting PRMT5 enzymatic activity with a small-molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARα and PGC-1α expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for the treatment of fatty liver.
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Affiliation(s)
- Lei Huang
- From the Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655
| | - Jehnan Liu
- the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio 43606
| | - Xiao-Ou Zhang
- the Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
| | - Katelyn Sibley
- the Department of Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts 01609, and
| | - Sonia M Najjar
- the Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio 43606.,the Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
| | - Mary M Lee
- From the Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655,
| | - Qiong Wu
- From the Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655,
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50
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Jing C, Cao H, Qin X, Yu S, Wu J, Wang Z, Ma R, Feng J. Exosome-mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR-21. Oncol Lett 2018; 15:9811-9817. [PMID: 29928355 DOI: 10.3892/ol.2018.8604] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 10/26/2017] [Indexed: 11/05/2022] Open
Abstract
Acquired resistance to gefitinib remains a major challenge in cancer treatment. In the present study, the effect of exosomes on the transmission of gefitinib resistance from gefitinib-resistant HCC827 lung cancer cells (H827R) to their gefitinib-sensitive counterparts and the potential underlying mechanisms by which this occurs was investigated. Exosomes were obtained from the cell supernatant using ultracentrifugation and the ExoQuick-TC exosome precipitation solution. Drug resistance was assessed by flow cytometry, apoptosis assays and cell counting kit-8 assays. The expression of microRNA (miR)-21 was analyzed by reverse transcription-quantitative polymerase chain reaction. Exosomes released by H827R cells (R/exo) may decrease the sensitivity of the human NSCLC HCC827 cell line to gefitinib. The results indicated that miR-21 expression was increased in R/exo and R/exo-treated H827S cells. However, miR-21 inhibition abrogated exosome-mediated drug resistance. Phosphorylated-protein kinase B (p-Akt), which is downstream of miR-21, was downregulated following gefitinib treatment; however, R/exo pretreatment elevated p-Akt levels and promoted the activation of Akt. By contrast, miR-21 inhibition reduced p-Akt expression. Therefore, the induction of miR-21 via exosomes and the activation of Akt may be mechanisms by which exosomes mediate the transfer of drug resistance.
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Affiliation(s)
- Changwen Jing
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Haixia Cao
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaobing Qin
- The Fourth Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Shaorong Yu
- Department of Chemotherapy, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Jianzhong Wu
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhuo Wang
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Rong Ma
- Clinical Cancer Research Center, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Jifeng Feng
- Department of Chemotherapy, Jiangsu Cancer Hospital, Cancer Institute of Jiangsu Province, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
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