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Zhang S, Hong HI, Mak VCY, Zhou Y, Lu Y, Zhuang G, Cheung LWT. Vertical inhibition of p110α/AKT and N-cadherin enhances treatment efficacy in PIK3CA-aberrated ovarian cancer cells. Mol Oncol 2025; 19:1132-1154. [PMID: 39543937 PMCID: PMC11977650 DOI: 10.1002/1878-0261.13761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/14/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024] Open
Abstract
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA, encoding PI3Kalpha (also known as p110α)] is one of the most commonly aberrated genes in human cancers. In serous ovarian cancer, PIK3CA amplification is highly frequent but PIK3CA point mutation is rare. However, whether PIK3CA amplification and PIK3CA driver mutations have the same functional impact in the disease is unclear. Here, we report that both PIK3CA amplification and E545K mutation are tumorigenic. While the protein kinase B (AKT) signaling axis was activated in both E545K knock-in cells and PIK3CA-overexpressing cells, the mitogen-activated protein kinase 3/1 (ERK1/2) pathway was induced selectively by E545K mutation but not PIK3CA amplification. Intriguingly, AKT signaling in these PIK3CA-aberrated cells increased transcriptional coactivator YAP1 (YAP) Ser127 phosphorylation and thereby cytoplasmic YAP levels, which in turn increased cell migration through Ras-related C3 botulinum toxin substrate 1 (RAC1) activation. In addition to the altered YAP signaling, AKT upregulated N-cadherin expression, which also contributed to cell migration. Pharmacological inhibition of N-cadherin reduced cell migratory potential. Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.
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Affiliation(s)
- Shibo Zhang
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongChina
- Sun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangzhouChina
| | - Hei Ip Hong
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongChina
| | - Victor C. Y. Mak
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongChina
| | - Yuan Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongChina
| | - Yiling Lu
- Division of Cancer Medicine, Department of Genomic MedicineUT MD Anderson Cancer CentreHoustonTXUSA
| | - Guanglei Zhuang
- State Key Laboratory of Systems Medicine for Cancer, Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Cancer InstituteShanghai Jiao Tong University School of MedicineChina
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji HospitalShanghai Jiao Tong University School of MedicineChina
| | - Lydia W. T. Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongChina
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Qiang M, Chen Z, Liu H, Dong J, Gong K, Zhang X, Huo P, Zhu J, Shao Y, Ma J, Zhang B, Liu W, Tang M. Targeting the PI3K/AKT/mTOR pathway in lung cancer: mechanisms and therapeutic targeting. Front Pharmacol 2025; 16:1516583. [PMID: 40041495 PMCID: PMC11877449 DOI: 10.3389/fphar.2025.1516583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.
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Affiliation(s)
- Min Qiang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Zhe Chen
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hongyang Liu
- College of Clinical Medicine, Jilin University, Changchun, China
| | - Junxue Dong
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kejian Gong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xinjun Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Peng Huo
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jingjun Zhu
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yifeng Shao
- Department of General Surgery, Capital Institute of Pediatrics’ Children’s Hospital, Beijing, China
| | - Jinazun Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Bowei Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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Ondič O, Michalová K, Švajdler M, Presl J, Kosťun J, Hájková V, Martínek P, Michal M. Molecular substratification of endometrial carcinomas with no special molecular profile (NSMP) by using a limited NGS custom panel may facilitate effective patient selection for the PIK3CA-targeted therapy. Virchows Arch 2024:10.1007/s00428-024-03905-6. [PMID: 39235514 DOI: 10.1007/s00428-024-03905-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/07/2024] [Accepted: 08/17/2024] [Indexed: 09/06/2024]
Abstract
Endometrial carcinomas (EC) of no special molecular profile (NSMP) represent the largest molecular category of EC, comprising a mixture of tumors with different histology and molecular profiles. These facts likely point to different tumor biology, clinical outcomes, and targeted therapy responses within this molecular category. The PIK3CA is currently the only targetable kinase oncoprotein directly implicated in EC carcinogenesis. Investigating a unique single-institution cohort, we attempted to stratify NSMP ECs based on the presence of the PIK3CA pathogenic mutation. Those cases were further analyzed for other well-established-associated oncogenic driver gene mutations. Histological and clinical variables were also correlated in each case. Altogether, 175 ECs were prospectively tested by a limited custom NGS panel containing ARID1A, BCOR, BRCA1, BRCA2, CTNNB1, KRAS, MLH1, MSH2, MSH6, NRAS, PIK3CA, PMS2, POLD1, POLE, PTEN,and TP53 genes. We identified 24 PIK3CA mutated cases in the group of 80 NSMP ECs, with another co-occurring mutation in at least one oncogenic driver gene (CTNNB1, PTEN, ARID1A, KRAS, BCOR, PMS2) in 19 cases. In conclusion, a limited NGS panel can effectively test EC tissue for specific pathogenetically relevant oncogene mutations. The NSMP EC category contains 30% of the PIK3CA mutated cases. Of those, 21% contain the PIK3CA mutation as a sole EC-associated oncogene mutation, while 79% harbor at least one more mutated gene. These findings may inform future healthcare planning and improve the effectiveness of EC patient selection for the PIK3CA-targeted therapy.
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Affiliation(s)
- Ondrej Ondič
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic.
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic.
| | - Květoslava Michalová
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Marián Švajdler
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Jiří Presl
- Department of Gynecology and Obstetrics, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
| | - Jan Kosťun
- Department of Gynecology and Obstetrics, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
| | - Veronika Hájková
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Petr Martínek
- Molecular Genetics Department, Bioptická Laboratoř s.r.o, Pilsen, Czech Republic
| | - Michal Michal
- Department of Pathology, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic
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Menges CW, Hassan D, Cheung M, Bellacosa A, Testa JR. Alterations of the AKT Pathway in Sporadic Human Tumors, Inherited Susceptibility to Cancer, and Overgrowth Syndromes. Curr Top Microbiol Immunol 2024. [PMID: 39192048 DOI: 10.1007/82_2024_278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
The AKT kinases are critical signaling molecules that regulate cellular physiology upon the activation of tyrosine kinase receptors and phosphatidylinositol 3-kinases (PI3K). AKT kinases govern many cellular processes considered hallmarks of cancer, including cell proliferation and survival, cell size, tumor invasion, metastasis, and angiogenesis. AKT signaling is regulated by multiple tumor suppressors and oncogenic proteins whose loss or activation, respectively, leads to dysregulation of this pathway, thereby contributing to oncogenesis. Herein, we review the enormous body of literature documenting how the AKT pathway becomes hyperactivated in sporadic human tumors and various hereditary cancer syndromes. We also discuss the role of activating mutations of AKT pathway genes in various chimeric overgrowth disorders, including Proteus syndrome, hypoglycemia with hypertrophy, CLOVES and SOLAMEN syndromes, and hemimegalencephaly.
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Affiliation(s)
- Craig W Menges
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Eurofins Lancaster Laboratories Professional Scientific Services, Lancaster, PA, 17601, USA
| | - Dalal Hassan
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
- Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Mitchell Cheung
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Alfonso Bellacosa
- Cancer Epigenetics Institute, Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Joseph R Testa
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
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Wang Y, Wen J, Sun X, Sun Y, Liu Y, Cheng X, Wu W, Liu Q, Ren F. CUDC-907 exhibits potent antitumor effects against ovarian cancer through multiple in vivo and in vitro mechanisms. Cancer Chemother Pharmacol 2024; 93:295-306. [PMID: 37938423 DOI: 10.1007/s00280-023-04610-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/16/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE CUDC-907 is a promising dual-target inhibitor of the HDAC and PI3K signaling pathways, with demonstrated therapeutic effects in a range of malignant tumors. However, its potential application in ovarian cancer (OC) has not been fully explored yet. In this study, we sought to investigate the efficacy of CUDC-907 in treating OC, both in vitro and in vivo. METHODS Here, we examined the correlation between PI3K or HDAC expression and the prognosis of OC patients using the GEPIA database. RNA-Seq analysis was performed on OC cells treated with CUDC-907.To assess various cellular processes, including proliferation, migration, invasion, apoptosis, and cell cycle, we performed a series of assays, including the CCK8, EDU, wound healing, cell invasion, and flow cytometry assays. Real-time quantitative PCR and western blotting were performed to measure the expressions of target genes. Additionally, we utilized the SKOV3 xenograft tumor model to investigate the inhibitory effects of CUDC-907 on tumor growth in vivo. RESULTS Bioinformatics analyses revealed that up-regulated HDAC and PI3K were significantly correlated with patients' poor survival in OC. In vivo and in vitro experiments have demonstrated that CUDC-907 could inhibit the proliferation of OC cells by inhibiting the PI3K and HDAC pathways to down-regulate the expression of c-Myc, and induce cell apoptosis by inhibiting the PI3K/AKT/Bcl-2 pathway, and up-regulate p21 to induce G2 /M phase arrest. CONCLUSION Our results showed that CUDC-907 had powerful anti-tumor effects on OC, which could provide a theoretical and experimental basis for the application of CUDC-907 in the therapy of OC.
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Affiliation(s)
- Yuanpei Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Jing Wen
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Xiangyi Sun
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yi Sun
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Yuchen Liu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Xiaoran Cheng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Weijia Wu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Qianwen Liu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China
| | - Fang Ren
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, People's Republic of China.
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Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023). Expert Opin Ther Pat 2024; 34:141-158. [PMID: 38557273 DOI: 10.1080/13543776.2024.2338100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 03/27/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. AREA COVERED This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. EXPERT OPINION To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.
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Affiliation(s)
- Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
- Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- National Center for Epidemics and Communicable Disease Control (JCDC), Amman, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, Jordan
| | - Haizhen A Zhong
- DSC 309, Department of Chemistry, The University of Nebraska at Omaha, Omaha, NE, USA
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Saeedi P, Eslami G, Tohidfar M, Jafari-Nodushan A, Vakili M. Differential gene expression (DGE) analysis in persons with a history of giardiasis. AMB Express 2024; 14:1. [PMID: 38170269 PMCID: PMC10764694 DOI: 10.1186/s13568-023-01657-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 12/17/2023] [Indexed: 01/05/2024] Open
Abstract
Giardiasis, which is caused by Giardia duodenalis, has clinical symptoms such as steatorrhea and can be very dangerous in children. In addition, some documents reported that this parasite is present inside the tissue of patients with cancer. In this study, we analyzed the gene expression profiles of some main genes important to apoptosis and anti-apoptosis in humans.Expression profile arrays of Genomic Spatial Event (GSE) 113666, GSE113667, and GSE113679 obtained from Gene Expression Omnibus were used for meta-analysis using R commands. Cytoscape and STRING databases used the protein-protein Interaction network. Then, the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis was performed. Similar genes in Homo sapiens were identified using Basic Local Alignment Search Tool analysis. The validation was performed on eight people using real-time Polymerase chain reaction. In addition to the candidate genes, the gene expression of some other genes, including Serine/Threonine Kinase 1 (AKT1), Cyclin Dependent Kinase Inhibitor 2A (CDKN2A), Kirsten Rat Sarcoma (KRAS), and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) were also examined. Analysis of the expression of serum amyloid A1 (SAA1), Regenerating Islet-Derived 3 Gamma (REG3G), and REG3A genes did not show any difference between the two groups of healthy and diseased people. Examining the mean expression of the four genes AKT1, CDKN2A, KRAS, and PIK3CA showed that three genes of AKT1, CDKN2A, and KRAS had increased expression in people with a history of giardiasis compared to healthy people. We showed that the gene expression pattern differs in apoptosis and anti-apoptosis signaling in people with a history of giardiasis. Giardia duodenalis seems to induce post-non-infectious symptoms with stimulation of human gene expression.
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Affiliation(s)
- Parnia Saeedi
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Gilda Eslami
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Masoud Tohidfar
- Department of Cell & Molecular Biology, Faculty of Life Sciences & Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - AbbasAli Jafari-Nodushan
- Department of Medical Parasitology and Mycology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahmood Vakili
- Department of Community and Preventive Medicine, Health Monitoring Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Yakubovich E, Cook DP, Rodriguez GM, Vanderhyden BC. Mesenchymal ovarian cancer cells promote CD8 + T cell exhaustion through the LGALS3-LAG3 axis. NPJ Syst Biol Appl 2023; 9:61. [PMID: 38086828 PMCID: PMC10716312 DOI: 10.1038/s41540-023-00322-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8+ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8+ T cells. We found CD8+ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.
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Affiliation(s)
- Edward Yakubovich
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada.
| | - David P Cook
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Galaxia M Rodriguez
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
| | - Barbara C Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
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Rani S, Lai A, Nair S, Sharma S, Handberg A, Carrion F, Möller A, Salomon C. Extracellular vesicles as mediators of cell-cell communication in ovarian cancer and beyond - A lipids focus. Cytokine Growth Factor Rev 2023; 73:52-68. [PMID: 37423866 DOI: 10.1016/j.cytogfr.2023.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023]
Abstract
Extracellular vesicles (EVs) are messengers that carry information in the form of proteins, lipids, and nucleic acids and are not only essential for intercellular communication but also play a critical role in the progression of various pathologies, including ovarian cancer. There has been recent substantial research characterising EV cargo, specifically, the lipid profile of EVs. Lipids are involved in formation and cargo sorting of EVs, their release and cellular uptake. Numerous lipidomic studies demonstrated the enrichment of specific classes of lipids in EVs derived from cancer cells suggesting that the EV associated lipids can potentially be employed as minimally invasive biomarkers for early diagnosis of various malignancies, including ovarian cancer. In this review, we aim to provide a general overview of the heterogeneity of EV, biogenesis, their lipid content, and function in cancer progression focussing on ovarian cancer.
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Affiliation(s)
- Shikha Rani
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Andrew Lai
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Soumya Nair
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Shayna Sharma
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Flavio Carrion
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - Andreas Möller
- Department of Otorhinolaryngology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia; Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile.
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10
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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11
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Bifarin O, Sah S, Gaul DA, Moore SG, Chen R, Palaniappan M, Kim J, Matzuk MM, Fernández FM. Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer. J Proteome Res 2023; 22:2092-2108. [PMID: 37220064 PMCID: PMC10243112 DOI: 10.1021/acs.jproteome.3c00226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Indexed: 05/25/2023]
Abstract
Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipid alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer.
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Affiliation(s)
- Olatomiwa
O. Bifarin
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, Georgia 30332, United States
| | - Samyukta Sah
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, Georgia 30332, United States
| | - David A. Gaul
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, Georgia 30332, United States
- Petit
Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Samuel G. Moore
- Petit
Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Ruihong Chen
- Department
of Pathology & Immunology, Baylor College
of Medicine, Houston, Texas 77030, United States
| | - Murugesan Palaniappan
- Department
of Pathology & Immunology, Baylor College
of Medicine, Houston, Texas 77030, United States
- Center
for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Jaeyeon Kim
- Department
of Biochemistry and Molecular Biology, Indiana University School of
Medicine, Indiana University Melvin and
Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
| | - Martin M. Matzuk
- Department
of Pathology & Immunology, Baylor College
of Medicine, Houston, Texas 77030, United States
- Center
for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Facundo M. Fernández
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, Georgia 30332, United States
- Petit
Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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12
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Zhang J, Croft J, Le A. Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations. J Pers Med 2023; 13:jpm13040673. [PMID: 37109059 PMCID: PMC10143507 DOI: 10.3390/jpm13040673] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/05/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.
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Affiliation(s)
- Jun Zhang
- Departments of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX 79905, USA
| | - Jacob Croft
- Departments of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX 79905, USA
| | - Alexander Le
- Departments of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX 79905, USA
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13
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Ma S, Cho S, Sahasranaman S, Zhao W, Pang J, Ding X, Dean B, Wang B, Hsu JY, Ware J, Salphati L. Absorption, Metabolism, and Excretion of Taselisib (GDC-0032), a Potent β-Sparing PI3K Inhibitor in Rats, Dogs, and Humans. Drug Metab Dispos 2023; 51:436-450. [PMID: 36623882 DOI: 10.1124/dmd.122.001096] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 01/11/2023] Open
Abstract
Taselisib (also known as GDC-0032) is a potent and selective phosphoinositide 3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα To better understand the absorption, distribution, metabolism, and excretion properties of taselisib, mass balance studies were conducted following single oral doses of [14C]taselisib in rats, dogs, and humans. Absolute bioavailability (ABA) of taselisib in humans was determined by oral administration of taselisib at the therapeutic dose followed by intravenous dosing of [14C]taselisib as a microtracer. The ABA in humans was 57.4%. Absorption of taselisib was rapid in rats and dogs and moderately slow in humans. The recovery of radioactivity in excreta was high (>96%) in the three species where feces was the major route of excretion. Taselisib was the major circulating component in the three species with no metabolite accounting for >10% of the total drug-derived material. The fraction absorbed of taselisib was 35.9% in rats and 71.4% in dogs. In rats, absorbed drug underwent moderate to extensive metabolism and biliary excretion of taselisib was minor. In dog, biliary excretion and metabolism were major clearance pathways. In humans, 84.2% of the dose was recovered as the parent drug in excreta indicating that metabolism played a minor role in the drug's clearance. Major metabolism pathways were oxidation and amide hydrolysis in the three species while methylation was another prominent metabolism pathway in dogs. The site of methylation was identified on the triazole moiety. In vitro experiments characterized that the N-methylation was dog-specific and likely mediated by a thiol methyltransferase. SIGNIFICANCE STATEMENT: This study provides a comprehensive description of the absorption, distribution, and metabolism and pharmacokinetic properties of taselisib in preclinical species and humans. This study demonstrated the importance of oral bioavailability results for understanding taselisib's clearance pathways. The study also describes the identification and characterization of a unique dog-specific N-methylation metabolite of taselisib and the enzyme mediating N-methylation in vitro.
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Affiliation(s)
- Shuguang Ma
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Sungjoon Cho
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Srikumar Sahasranaman
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Weiping Zhao
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Jodie Pang
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Xiao Ding
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Brian Dean
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Bin Wang
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Jerry Y Hsu
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Joseph Ware
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
| | - Laurent Salphati
- Department of Drug Metabolism and Pharmacokinetics (S.M., S.C., W.Z., J.P., X.D., B.D., L.S.) and Department of Clinical Pharmacology (S.S., J.Y.H., J.W.), Genentech, Inc., South San Francisco, California; and XenoBiotic Laboratories (B.W.), Inc., Plainsboro, New Jersey
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14
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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: 0] [Impact Index Per Article: 0] [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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15
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Bifarin OO, Sah S, Gaul DA, Moore SG, Chen R, Palaniappan M, Kim J, Matzuk MM, Fernández FM. Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.04.520434. [PMID: 36711577 PMCID: PMC9881992 DOI: 10.1101/2023.01.04.520434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages, and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipids alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer. Teaser Time-resolved lipidome remodeling in an ovarian cancer model is studied through lipidomics and machine learning.
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Affiliation(s)
- Olatomiwa O. Bifarin
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Samyukta Sah
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - David A. Gaul
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Samuel G. Moore
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Ruihong Chen
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Murugesan Palaniappan
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Jaeyeon Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, 46202, United States
| | - Martin M. Matzuk
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States
- Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Facundo M. Fernández
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
- Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
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16
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Skorda A, Bay ML, Hautaniemi S, Lahtinen A, Kallunki T. Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises. Cancers (Basel) 2022; 14:6257. [PMID: 36551745 PMCID: PMC9777107 DOI: 10.3390/cancers14246257] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors to supplement the standard platinum- and taxane-based chemotherapy, the expected overall survival of HGSC patients has not improved significantly from the five-year rate of 42%. This calls for the development and testing of more efficient treatment options. Many oncogenic kinase-signaling pathways are dysregulated in HGSC. Since small-molecule kinase inhibitors have revolutionized the treatment of many solid cancers due to the generality of the increased activation of protein kinases in carcinomas, it is reasonable to evaluate their potential against HGSC. Here, we present the latest concluded and on-going clinical trials on kinase inhibitors in HGSC, as well as the recent work concerning ovarian cancer patient organoids and xenograft models. We discuss the potential of kinase inhibitors as personalized treatments, which would require comprehensive assessment of the biological mechanisms underlying tumor spread and chemoresistance in individual patients, and their connection to tumor genome and transcriptome to establish identifiable subgroups of patients who are most likely to benefit from a given therapy.
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Affiliation(s)
- Aikaterini Skorda
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - Marie Lund Bay
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
| | - Sampsa Hautaniemi
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Alexandra Lahtinen
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Tuula Kallunki
- Cancer Invasion and Resistance Group, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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17
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Gunel NS, Yildirim N, Ozates NP, Oktay LM, Bagca BG, Sogutlu F, Ozsaran A, Korkmaz M, Biray Avci C. Investigation of cytotoxic and apoptotic effects of disodium pentaborate decahydrate on ovarian cancer cells and assessment of gene profiling. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:8. [PMID: 36308567 DOI: 10.1007/s12032-022-01870-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/20/2022] [Indexed: 01/17/2023]
Abstract
After revealing the anti-cancer properties of boron, which is included in the category of essential elements for human health by the World Health Organization, the therapeutic potential of boron compounds has been begun to be evaluated, and its molecular effect mechanisms have still been among the research subjects. In ovarian cancer, mutations or amplifications frequently occur in the PI3K/Akt/mTOR pathway components, and dysregulation of this pathway is shown among the causes of treatment failure. In the present study, it was aimed to investigate the anti-cancer properties of boron-containing DPD in SKOV3 cells, which is an epithelial ovarian cancer model, through PI3K/AKT/mTOR pathway. The cytotoxic activity of DPD in SKOV3 cells was evaluated by WST-1 test, apoptotic effect by Annexin V and JC-1 test. The gene expressions associated with PI3K/AKT/mTOR pathway were determined by real-time qRT-PCR. In SKOV3 cells, the IC50 value of DPD was found to be 6.7 mM, 5.6 mM, and 5.2 mM at 24th, 48th and 72nd hour, respectively. Compared with the untreated control group, DPD treatment was found to induce apoptosis 2.6-fold and increase mitochondrial membrane depolarization 4.5-fold. DPD treatment was found to downregulate PIK3CA, PIK3CG, AKT2, IGF1, IRS1, MAPK3, HIF-1, VEGFC, CAB39, CAB39L, STRADB, PRKAB2, PRKAG3, TELO2, RICTOR, MLST8, and EIF4B genes and upregulate TP53, GSK3B, FKBP8, TSC2, ULK1, and ULK2 genes. These results draw attention to the therapeutic potential of DPD, which is frequently exposed in daily life, in epithelial ovarian cancer and show that it can be a candidate compound in combination with chemotherapeutics.
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Affiliation(s)
- Nur Selvi Gunel
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey
| | - Nuri Yildirim
- Department of Obstetrics and Gynecology, Medicine Faculty, Ege University, Izmir, Turkey
| | | | - Latife Merve Oktay
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey
| | - Bakiye Goker Bagca
- Department of Medical Biology, Medicine Faculty, Adnan Menderes University, Izmir, Turkey
| | - Fatma Sogutlu
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey
| | - Aydin Ozsaran
- Department of Obstetrics and Gynecology, Medicine Faculty, Ege University, Izmir, Turkey
| | - Mehmet Korkmaz
- Department of Medical Biology, Medicine Faculty, Celal Bayar University, Manisa, Turkey
| | - Cigir Biray Avci
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey.
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18
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Farah AM, Gu S, Jia Y. Clinical analysis and literature review of a case of ovarian clear cell carcinoma with PIK3CA gene mutation: A case report. Medicine (Baltimore) 2022; 101:e30666. [PMID: 36123851 PMCID: PMC9478318 DOI: 10.1097/md.0000000000030666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Ovarian clear cell carcinoma (OCCC) is an uncommon malignant form of 5 subtypes of ovarian cancer, accounting for approximately 5% to 25% of all ovarian cancers. OCCC is usually diagnosed at a young age and an early stage. More than 50% of patients are associated with endometriosis. It shows less sensitivity to platinum-based chemotherapies, high recurrence, and poor prognosis, especially late. However, platinum-based chemotherapies remain the first-line treatment. Meanwhile, new treatment modalities have been explored, including immune checkpoint inhibitors and PI3K-AKT-mTOR pathway inhibitors. PATIENT CONCERN A 48-year-old Chinese woman, Gravida2 Para1, complained of irregular and painful vaginal bleeding for 4 months. DIAGNOSIS The patient was diagnosed with stage IC ovarian clear cell carcinoma that presented with a mutation of the phosphatidylinositol 4,5-bisphosphate 3-kinase alpha subunit (PIK3CA) gene. INTERVENTION We performed an early diagnosis and complete surgical resection of the tumor with platinum-based chemotherapy. OUTCOME This patient with mutation of the PIK3CA gene was sensitive to platinum-based chemotherapy, showed a significant downwards trend in tumor markers, and was in good health within the year of follow-up. LESSONS This study described an OCCC case that presented with a PIK3CA mutation and was successfully managed with careful and complete resection of the tumor. This patient with mutation of the PIK3CA gene was sensitive to platinum-based chemotherapy, showed a significant downwards trend in tumor markers, and did not have recurrence after a year of follow-up, indicating a reasonably good prognosis. Therefore, surgery plus platinum drug chemotherapy is still the best strategy for OCCC treatment. In addition, it is recommended for such patients to undergo genetic testing as much as possible to predict the clinical treatment effect.
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Affiliation(s)
- Abdulkarim Mohamed Farah
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
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19
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The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol 2022; 127:104787. [DOI: 10.1016/j.yexmp.2022.104787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/15/2022] [Accepted: 05/21/2022] [Indexed: 01/02/2023]
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20
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Gao J, Fu Y, Song L, Long M, Zhang Y, Qin J, Liu H. Proapoptotic Effect of Icariin on Human Ovarian Cancer Cells via the NF-[Formula: see text]B/PI3K-AKT Signaling Pathway: A Network Pharmacology-Directed Experimental Investigation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:589-619. [PMID: 35114909 DOI: 10.1142/s0192415x22500239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Based on network pharmacology tools and public bioinformatics databases, the pharmacodynamic target and key mechanism of icariin (ICA) in the treatment of ovarian cancer (OC) were identified and experimentally verified. Our previous research showed that TNF, MMP9, STAT3, PIK3CA, ERBB2, MTOR, IL2, PTGS2, KDR and F2 are important targets of ICA in the treatment of OC. TNF, as a hub gene in tumor tissues, was associated with poor prognosis. ICA acted on OC mainly through the biological functions of various kinases, and the pathway with the highest accuracy ([Formula: see text]-value) was PI3K. Meanwhile, we observed a close upstream and downstream relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. This study further verified the mechanism of ICA in promoting apoptosis of SKOV3 cells through the NF-[Formula: see text]B signaling pathway and the tandem relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. The assay results demonstrated that ICA can promote the apoptosis of SKOV3 cells as indicated by the proapoptotic markers Bax, Bcl-xl and Caspase-3 and the key factors of the NF-[Formula: see text]B signaling pathway (NF-[Formula: see text]Bp65, p-NF-[Formula: see text]Bp65, p-I[Formula: see text]B[Formula: see text] and I[Formula: see text]B[Formula: see text]. ICA can block the classical NF-[Formula: see text]B pathway by inhibiting I[Formula: see text]B[Formula: see text] phosphorylation and consequently blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells. ICA can also promote apoptosis by blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells via inhibition of NF-[Formula: see text]Bp65 nuclear translocation. After using a PI3K pathway inhibitor, we further discovered that ICA may reduce AKT signal transduction by inhibiting the level of Akt phosphorylation, resulting in a loss of PI3K/Akt-dependent activation of the NF-[Formula: see text]B pathway.
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Affiliation(s)
- Jingjing Gao
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Yanjin Fu
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Linliang Song
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Mengsha Long
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Yiyao Zhang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Jiajia Qin
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P. R. China
| | - Haiquan Liu
- Guangzhou University of Traditional Chinese Medicine, Huizhou Traditional Chinese Medicine Hospital, Huizhou, Guangdong 516001, P. R. China
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Krop IE, Jegede OA, Grilley-Olson JE, Lauring JD, Mitchell EP, Zwiebel JA, Gray RJ, Wang V, McShane LM, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Kono SA, Ford JM, Garcia AA, Sui XD, Siegel RD, Slomovitz BM, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT. Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I. JCO Precis Oncol 2022; 6:e2100424. [PMID: 35138919 PMCID: PMC8865530 DOI: 10.1200/po.21.00424] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/12/2021] [Accepted: 01/05/2022] [Indexed: 01/14/2023] Open
Abstract
PURPOSE PIK3CA mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in PIK3CA-mutant breast cancer. Whether PIK3CA mutations predict sensitivity to taselisib in other cancer types is unknown. National Cancer Institute-Molecular Analysis for Therapy Choice Arm EAY131-I is a single-arm, phase II study of the safety and efficacy of taselisib in patients with advanced cancers. METHODS Eligible patients had tumors with an activating PIK3CA mutation. Patients with breast or squamous cell lung carcinoma, or whose cancer had KRAS or PTEN mutations, were excluded. Patients received taselisib 4 mg, orally once daily continuously, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival (OS), and identification of predictive biomarkers. RESULTS Seventy patients were enrolled, and 61 were eligible and initiated protocol therapy. Types of PIK3CA mutations included helical 41 of 61 (67%), kinase 11 of 61 (18%), and other 9 of 61 (15%). With a median follow-up of 35.7 months, there were no complete or partial responses. Six-month PFS was 19.9% (90% CI, 12.0 to 29.3) and median PFS was 3.1 months (90% CI, 1.8 to 3.7). Six-month OS was 60.7% (90% CI, 49.6 to 70.0) and median OS was 7.2 months (90% CI, 5.9 to 10.0). Individual comutations were too heterogeneous to correlate with clinical outcome. Fatigue, diarrhea, nausea, and hyperglycemia were the most common toxicities, and most were grade 1 and 2. CONCLUSION In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA-mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity.
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Affiliation(s)
- Ian E. Krop
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Opeyemi A. Jegede
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
| | | | | | | | | | - Robert J. Gray
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
| | - Victoria Wang
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, MA
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22
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Zhang X, Qi W, Xu Q, Li X, Zhou L, Ye L. Di(2-ethylhexyl) phthalate (DEHP) and thyroid: biological mechanisms of interference and possible clinical implications. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:1634-1644. [PMID: 34677768 DOI: 10.1007/s11356-021-17027-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 10/10/2021] [Indexed: 05/15/2023]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental endocrine disruptor. DEHP can be absorbed into the human body through the air, food, water, and skin. After entering the human body, DEHP is rapidly converted to mono(2-ethylhexyl) phthalate (MEHP) with greater toxicity than DEHP. An increasing number of studies indicates that DEHP or MEHP can damage the thyroid tissue and disrupt the function, but the mechanisms remain unclear. This article reviews the toxicity of DEHP on thyroid structures and functions and summarizes the potential mechanisms to provide evidence for preventing the thyroid-related diseases.
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Affiliation(s)
- Xueting Zhang
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China
| | - Wen Qi
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China
| | - Qi Xu
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China
| | - Xu Li
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China
| | - Liting Zhou
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China
| | - Lin Ye
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China.
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23
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Li H, Fang H, Chang L, Qiu S, Ren X, Cao L, Bian J, Wang Z, Guo Y, Lv J, Sun Z, Wang T, Li B. TC2N: A Novel Vital Oncogene or Tumor Suppressor Gene In Cancers. Front Immunol 2021; 12:764749. [PMID: 34925334 PMCID: PMC8674203 DOI: 10.3389/fimmu.2021.764749] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
Several C2 domain-containing proteins play key roles in tumorigenesis, signal transduction, and mediating protein–protein interactions. Tandem C2 domains nuclear protein (TC2N) is a tandem C2 domain-containing protein that is differentially expressed in several types of cancers and is closely associated with tumorigenesis and tumor progression. Notably, TC2N has been identified as an oncogene in lung and gastric cancer but as a tumor suppressor gene in breast cancer. Recently, a large number of tumor-associated antigens (TAAs), such as heat shock proteins, alpha-fetoprotein, and carcinoembryonic antigen, have been identified in a variety of malignant tumors. Differences in the expression levels of TAAs between cancer cells and normal cells have led to these antigens being investigated as diagnostic and prognostic biomarkers and as novel targets in cancer treatment. In this review, we summarize the clinical characteristics of TC2N-positive cancers and potential mechanisms of action of TC2N in the occurrence and development of specific cancers. This article provides an exploration of TC2N as a potential target for the diagnosis and treatment of different types of cancers.
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Affiliation(s)
- Hanyang Li
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, China
| | - He Fang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Li Chang
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Shuang Qiu
- Department of Biobank, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiaojun Ren
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Lidong Cao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jinda Bian
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Zhenxiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yi Guo
- Department of Breast Surgery, The Affiliated Hospital Changchun University of Chinese Medicine, Changchun, China
| | - Jiayin Lv
- Department of Orthopedics, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhihui Sun
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun, China
| | - Tiejun Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Tiejun Wang, ; Bingjin Li,
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Tiejun Wang, ; Bingjin Li,
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24
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George J, Li Y, Kadamberi IP, Parashar D, Tsaih SW, Gupta P, Geethadevi A, Chen C, Ghosh C, Sun Y, Mittal S, Ramchandran R, Rui H, Lopez-Berestein G, Rodriguez-Aguayo C, Leone G, Rader JS, Sood AK, Dey M, Pradeep S, Chaluvally-Raghavan P. RNA-binding protein FXR1 drives cMYC translation by recruiting eIF4F complex to the translation start site. Cell Rep 2021; 37:109934. [PMID: 34731628 PMCID: PMC8675433 DOI: 10.1016/j.celrep.2021.109934] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/02/2021] [Accepted: 10/12/2021] [Indexed: 11/17/2022] Open
Abstract
Fragile X-related protein-1 (FXR1) gene is highly amplified in patients with ovarian cancer, and this amplification is associated with increased expression of both FXR1 mRNA and protein. FXR1 expression directly associates with the survival and proliferation of cancer cells. Surface sensing of translation (SUnSET) assay demonstrates that FXR1 enhances the overall translation in cancer cells. Reverse-phase protein array (RPPA) reveals that cMYC is the key target of FXR1. Mechanistically, FXR1 binds to the AU-rich elements (ARE) present within the 3' untranslated region (3'UTR) of cMYC and stabilizes its expression. In addition, the RGG domain in FXR1 interacts with eIF4A1 and eIF4E proteins. These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.
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Affiliation(s)
- Jasmine George
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Yongsheng Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China
| | - Ishaque P Kadamberi
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shirng-Wern Tsaih
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Prachi Gupta
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Anjali Geethadevi
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Changliang Chen
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Chandrima Ghosh
- Department of Biological Sciences, University of Wisconsin, Milwaukee, WI 53211, USA
| | - Yunguang Sun
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sonam Mittal
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ramani Ramchandran
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Hallgeir Rui
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Gustavo Leone
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA
| | - Janet S Rader
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Anil K Sood
- Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Department of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Madhusudan Dey
- Department of Biological Sciences, University of Wisconsin, Milwaukee, WI 53211, USA
| | - Sunila Pradeep
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA
| | - Pradeep Chaluvally-Raghavan
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA.
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25
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Hong C, Khan M, Sukys J, Prasad M, Erson-Omay EZ, Vining E, Omay SB. PIK3CA mutation in a case of CTNNB1 mutant sinonasal glomangiopericytoma. Cold Spring Harb Mol Case Stud 2021; 8:mcs.a006120. [PMID: 34667073 PMCID: PMC8744496 DOI: 10.1101/mcs.a006120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/30/2021] [Indexed: 11/24/2022] Open
Abstract
Glomangiopericytomas are rare, primary sinonasal tumors. The existing literature is mostly limited to reports describing the clinicopathologic characteristics of these tumors. Comprehensive genetic characterization of glomangiopericytomas remain lacking. Whole exome sequencing of a case of glomangiopericytoma was performed under an institutional review board approved protocol. A 69 year-old female underwent surgical resection of a glomangiopericytoma. Whole exome sequencing revealed somatic mutations in CTNNB1 and PIK3CA, the former previously associated with this pathology but the latter not described. Concurrent dysregulation of Wnt/beta-catenin and PI3K/AKT/mTOR signaling, secondary to mutations in these two oncogenes may be amenable to targeted treatment with existing clinically approved drugs. Genomic characterization of glomangiopericytomas remains lacking. This study reports novel co-existence of PIK3CA and CTNNB1 mutations in a case of glomangiopericytoma that may offer insight into the pathogenesis and potential for targeted medical therapies of this rare tumor.
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Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov 2021; 20:741-769. [PMID: 34127844 PMCID: PMC9297732 DOI: 10.1038/s41573-021-00209-1] [Citation(s) in RCA: 253] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2021] [Indexed: 01/08/2023]
Abstract
Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
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Affiliation(s)
| | - Matthew W D Perry
- Medicinal Chemistry, Research and Early Development, Respiratory & Immunology BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jennifer R Brown
- CLL Center, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Fabrice André
- Institut Gustave Roussy, INSERM U981, Université Paris Saclay, Paris, France
| | - Klaus Okkenhaug
- Department of Pathology, University of Cambridge, Cambridge, UK
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Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance. Cancers (Basel) 2021; 13:cancers13174363. [PMID: 34503172 PMCID: PMC8430856 DOI: 10.3390/cancers13174363] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/21/2021] [Accepted: 08/26/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Despite recent therapeutic advances against cancer, many patients do not respond well or respond poorly, to treatment and develop resistance to more than one anti-cancer drug, a term called multi-drug resistance (MDR). One of the main factors that contribute to MDR is the deregulation of apoptosis or programmed cell death. Herein, we describe the major apoptotic pathways and discuss how pro-apoptotic and anti-apoptotic proteins are modified in cancer cells to convey drug resistance. We also focus on our current understanding related to the interactions between survival and cell death pathways, as well as on mechanisms underlying the balance shift towards cancer cell growth and drug resistance. Moreover, we highlight the role of the tumor microenvironment components in blocking apoptosis in MDR tumors, and we discuss the significance and potential exploitation of epigenetic modifications for cancer treatment. Finally, we summarize the current and future therapeutic approaches for overcoming MDR. Abstract The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI3K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype.
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28
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Rascio F, Spadaccino F, Rocchetti MT, Castellano G, Stallone G, Netti GS, Ranieri E. The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review. Cancers (Basel) 2021; 13:3949. [PMID: 34439105 PMCID: PMC8394096 DOI: 10.3390/cancers13163949] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.
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Affiliation(s)
- Federica Rascio
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Federica Spadaccino
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Maria Teresa Rocchetti
- Cell Biology Unit, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Giuseppe Castellano
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (G.C.); (G.S.)
| | - Giuseppe Stefano Netti
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
| | - Elena Ranieri
- Clinical Pathology Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (F.S.); (G.S.N.); (E.R.)
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29
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Bolitho C, Moscova M, Baxter RC, Marsh DJ. Amphiregulin increases migration and proliferation of epithelial ovarian cancer cells by inducing its own expression via PI3-kinase signaling. Mol Cell Endocrinol 2021; 533:111338. [PMID: 34062166 DOI: 10.1016/j.mce.2021.111338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/09/2022]
Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer, including epithelial ovarian cancer (EOC), and its expression has been found to correlate with advanced stage and poor prognosis. The EGFR ligand amphiregulin (AREG) has been investigated as a target for human cancer therapy and is known to have an autocrine role in many cancers. A cytokine array identified AREG as one of several cytokines upregulated by EGF in a phosphatidylinositol 3-kinase (PI3-K) dependent manner in EOC cells. To investigate the functional role of AREG in EOC, its effect on cellular migration and proliferation was assessed in two EOC cells lines, OV167 and SKOV3. AREG increased both migration and proliferation of EOC cell line models through activation of PI3-K signaling, but independent of mitogen activated protein kinase (MAPK) signaling. Through an AREG autocrine loop mediated via PI3-K, upregulation of AREG led to increased levels of both AREG transcript and secreted AREG, while downregulation of endogenous AREG decreased the ability of exogenous AREG to induce cell migration and proliferation. Further, inhibition of endogenous AREG activity or metalloproteinase activity decreased EGF-induced EOC migration and proliferation, indicating a role for soluble endogenous AREG in mediating the functional effects of EGFR in inducing migration and proliferation in EOC.
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Affiliation(s)
- Christine Bolitho
- University of Sydney, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia
| | - Michelle Moscova
- University of Sydney, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; School of Medical Sciences, University of New South Wales, Sydney, Kensington, NSW, 2052, Australia
| | - Robert C Baxter
- University of Sydney, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia
| | - Deborah J Marsh
- Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology, Sydney, Ultimo, NSW, 2007, Australia; Northern Clinical School, Kolling Institute, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
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Chaput L, Jordheim LP. [Current landscape of biomarker development for immune checkpoint inhibitors targeting PD-1/PD-L1 pathway in oncology]. Therapie 2021; 76:597-615. [PMID: 34332787 DOI: 10.1016/j.therap.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/25/2021] [Accepted: 06/29/2021] [Indexed: 12/26/2022]
Abstract
The immune checkpoints inhibitors targeting PD-1 or PD-L1 represent a new paradigm in the cancer treatment strategy. However, some populations of patients do not benefit from these agents. The identification of predictive biomarkers appears as an essential step for the treatment pathway, to guarantee the access to an evidence-based medicine accounting for the potential toxicity profile, the cost for the healthcare system and the clinical benefit eventually provided by these new drugs. In this review, we propose, based on scientific literature and industrial communications, an overview of the current landscape of predictive biomarkers related to PD-1 or PD-L1 inhibitors efficacy, validated or under development, their evidence level, and limits accounting for identified or potential confounding factors. Our paper shows that, despite the important amount of work performed in this field, there is not yet a validated and efficient solution for the prediction of the activity and/or the toxicity of anti-PD-1 and anti-PD-L1 antibodies.
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Affiliation(s)
- Lisa Chaput
- Université Lyon, université Claude-Bernard Lyon 1, faculté de pharmacie de Lyon, ISPB, 69008 Lyon, France
| | - Lars Petter Jordheim
- Université Lyon, université Claude-Bernard Lyon 1, faculté de pharmacie de Lyon, ISPB, 69008 Lyon, France; Université Lyon, université Claude-Bernard Lyon 1, INSERM 1052, CNRS 5286, centre Léon-Bérard, centre de recherche en cancérologie de Lyon, 69008 Lyon, France.
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Afify SM, Oo AKK, Hassan G, Seno A, Seno M. How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer. Expert Rev Anticancer Ther 2021; 21:605-619. [PMID: 33857392 DOI: 10.1080/14737140.2021.1918001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a fundamental regulator of cell proliferation and survival. Dysregulation in this pathway leads to the development of cancer. Accumulating evidence indicates that dysregulation in this pathway is involved in cancer initiation, progression, and recurrence. However, the pathway consists of various signal transducing factors related with cellular events, such as transformation, tumorigenesis, cancer progression, and drug resistance. Therefore, it is very important to determine the targets in this pathway for cancer therapy. Although many drugs inhibiting this signaling pathway are in clinical trials or have been approved for treating solid tumors and hematologic malignancies, further understanding of the signaling mechanism is required to achieve better therapeutic efficacy.Areas covered: In this review, we have describe the PI3K/AKT/mTOR pathway in detail, along with its critical role in cancer stem cells, for identifying potential therapeutic targets. We also summarize the recent developments in different types of signaling inhibitors.Expert opinion: Downregulation of the PI3K/AKT/mTOR pathway is very important for treating all types of cancers. Thus, further studies are required to establish novel prognostic factors to support the current progress in cancer treatment with emphasis on this pathway.
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Affiliation(s)
- Said M Afify
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan.,Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin, El Kom-Menoufia, Egypt
| | - Aung Ko Ko Oo
- Department of Biotechnology, Mandalay Technological University, Mandalay, Myanmar
| | - Ghmkin Hassan
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan.,Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus, Syria
| | - Akimasa Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
| | - Masaharu Seno
- Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
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Ma J, Zhang L, Chen J, Song B, Zang C, Liu H. m 7GDisAI: N7-methylguanosine (m 7G) sites and diseases associations inference based on heterogeneous network. BMC Bioinformatics 2021; 22:152. [PMID: 33761868 PMCID: PMC7992861 DOI: 10.1186/s12859-021-04007-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background Recent studies have confirmed that N7-methylguanosine (m7G) modification plays an important role in regulating various biological processes and has associations with multiple diseases. Wet-lab experiments are cost and time ineffective for the identification of disease-associated m7G sites. To date, tens of thousands of m7G sites have been identified by high-throughput sequencing approaches and the information is publicly available in bioinformatics databases, which can be leveraged to predict potential disease-associated m7G sites using a computational perspective. Thus, computational methods for m7G-disease association prediction are urgently needed, but none are currently available at present. Results To fill this gap, we collected association information between m7G sites and diseases, genomic information of m7G sites, and phenotypic information of diseases from different databases to build an m7G-disease association dataset. To infer potential disease-associated m7G sites, we then proposed a heterogeneous network-based model, m7G Sites and Diseases Associations Inference (m7GDisAI) model. m7GDisAI predicts the potential disease-associated m7G sites by applying a matrix decomposition method on heterogeneous networks which integrate comprehensive similarity information of m7G sites and diseases. To evaluate the prediction performance, 10 runs of tenfold cross validation were first conducted, and m7GDisAI got the highest AUC of 0.740(± 0.0024). Then global and local leave-one-out cross validation (LOOCV) experiments were implemented to evaluate the model’s accuracy in global and local situations respectively. AUC of 0.769 was achieved in global LOOCV, while 0.635 in local LOOCV. A case study was finally conducted to identify the most promising ovarian cancer-related m7G sites for further functional analysis. Gene Ontology (GO) enrichment analysis was performed to explore the complex associations between host gene of m7G sites and GO terms. The results showed that m7GDisAI identified disease-associated m7G sites and their host genes are consistently related to the pathogenesis of ovarian cancer, which may provide some clues for pathogenesis of diseases. Conclusion The m7GDisAI web server can be accessed at http://180.208.58.66/m7GDisAI/, which provides a user-friendly interface to query disease associated m7G. The list of top 20 m7G sites predicted to be associted with 177 diseases can be achieved. Furthermore, detailed information about specific m7G sites and diseases are also shown. Supplementary Information The online version contains supplementary material available at 10.1186/s12859-021-04007-9.
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Affiliation(s)
- Jiani Ma
- Engineering Research Center of Intelligent Control for Underground Space, Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China.,School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China
| | - Lin Zhang
- Engineering Research Center of Intelligent Control for Underground Space, Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China. .,School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China.
| | - Jin Chen
- Engineering Research Center of Intelligent Control for Underground Space, Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China.,School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China
| | - Bowen Song
- Department of Biological Sciences, AI University Research Center, Xi'an Jiaotong-Liverpool University, Suzhou, 215123, China
| | - Chenxuan Zang
- Department of Biological Sciences, AI University Research Center, Xi'an Jiaotong-Liverpool University, Suzhou, 215123, China
| | - Hui Liu
- Engineering Research Center of Intelligent Control for Underground Space, Ministry of Education, China University of Mining and Technology, Xuzhou, 221116, China.,School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China
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Al-Qahtani WS, Alduwish MA, Al-Olayan EM, Aljarba NH, Em AH, Albani FG, Domiaty DM, Al-Otaibi AM, Qattan SMA, Almurshedi AS, Elasbali AM, Ahmed HG, Almutlaq BA. Screening for PIK3CA mutations among Saudi women with ovarian cancer. J OBSTET GYNAECOL 2021; 41:1127-1133. [PMID: 33475035 DOI: 10.1080/01443615.2020.1839871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The study aimed to screen for PIK3CA gene mutations among Saudi women with Ovarian Cancer. The study included 298 Saudi women with epithelial ovarian cancers (EOC). DNA sequence analysis was employed to screen for the mutations. DNA sequence analysis of a coding region of exon 9 and 20 of PIK3CA gene revealed mutations in 37/298 (12.4%) EOC patients. About 21/37(56.8%) somatic mutations were identified in exons 9, and 16/37(43.2%) in exon 20. All analysed mutations were missense mutations, the frequencies of which varied from 2.7% to 43.2%. PIK3CA mutation was found to be significantly associated with age (p = .023), grade (p = .001) and histological types (p = .032). Only 6.6% of serous carcinomas and 3.8% of endometrioid had PIK3CA mutation. The Mutated PIK3CA gene was significantly involved in the pathogenesis of EOC among Saudi women. PIK3CA gene mutation and overexpression represent important clinical implications for diagnosis, and prognosis, which can be utilised for better EOC management.Impact statementWhat is already known on this subject? The detailed molecular and genetic phenomenon underlying the progression of these tumours is still unclear. Recently, the pathogenesis of ovarian cancer has been attributed to mutations of PIK3CA.What do the results of this study add? Mutation in the PIK3CA gene leads to altered PI3K/AKT signalling pathways responsible for the progression of the epithelial ovarian cancer.What are the implications of these findings for clinical practice and/or further research? The Mutated PIK3CA gene was significantly involved in the pathogenesis of EOC among Saudi women. PIK3CA gene mutation and overexpression represent important clinical implications for diagnosis, and prognosis, which can be utilised for better EOC management.
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Affiliation(s)
- Wedad Saeed Al-Qahtani
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University of Security Sciences, Riyadh, Saudi Arabia
| | - Manal Abduallah Alduwish
- Department of Biology, College of Science and Humanities, Prince Sattam bin Abdulaziz University, Alkarj, Saudi Arabia
| | - Ebtesam M Al-Olayan
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Nada Hamad Aljarba
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Al-Humaidhi Em
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Fatimah Gh Albani
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Dalia Mostafa Domiaty
- Department of Biology, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Aljohara M Al-Otaibi
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Somaya M Al Qattan
- King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh, Saudi Arabia
| | - Alanood S Almurshedi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdelbaset Mohamed Elasbali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Qurayyat, Saudi Arabia
| | - Hussain Gadelkarim Ahmed
- College of Medicine, University of Hail, Hail, Saudi Arabia.,Molecular Diagnostics and Personalized Therapeutics Unit, University of Ha'il, Hail, Saudi Arabia.,Department of Histopathology and Cytology, FMLS, University of Khartoum, Khartoum, Sudan
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Nisar S, Hashem S, Macha MA, Yadav SK, Muralitharan S, Therachiyil L, Sageena G, Al-Naemi H, Haris M, Bhat AA. Exploring Dysregulated Signaling Pathways in Cancer. Curr Pharm Des 2020; 26:429-445. [PMID: 31939726 DOI: 10.2174/1381612826666200115095937] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]
Abstract
Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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Affiliation(s)
- Sabah Nisar
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States.,Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Santosh K Yadav
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Hamda Al-Naemi
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
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Liu J, Meng H, Nie S, Sun Y, Jiang P, Li S, Yang J, Sun R, Cheng W. Identification of a prognostic signature of epithelial ovarian cancer based on tumor immune microenvironment exploration. Genomics 2020; 112:4827-4841. [PMID: 32890701 DOI: 10.1016/j.ygeno.2020.08.027] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/24/2020] [Accepted: 08/21/2020] [Indexed: 12/22/2022]
Abstract
This study aims to develop an immune-related genes (IRGs) prognostic signature to stratify the epithelial ovarian cancer (EOC) patients. We identified 332 up- and 154 down-regulated EOC-specific IRGs. As a result, candidate IRGs were idendified to construct prognostic models respectivy for overall survial and progression-free survival. The risk score was validated as a risk factor for prognosis and was used to built a combined nomogram. According to the IRG-related prognostic model, EOC patients were divided into high- and low- risk group and were further explored their association with tumor immune microenvironment (TME). CIBERSORT algorithm showed higher macrophages M1 cell, T cells follicular helper cell and plasma cells infiltrating levels in the low-risk group. In addition, the low-risk group was found with higher immunophenoscore and distinct mutation signatures compared with the high-risk group. These findings may shed light on the development of novel immune biomarkers and target therapy of EOC.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Huangyang Meng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Sipei Nie
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Ying Sun
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Pinping Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Siyue Li
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Jing Yang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Rui Sun
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Wenjun Cheng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
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Zou M, Jin R, Au KF. Revealing tumor heterogeneity of breast cancer by utilizing the linkage between somatic and germline mutations. Brief Bioinform 2020; 20:2306-2315. [PMID: 30239581 PMCID: PMC6954402 DOI: 10.1093/bib/bby084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 06/07/2018] [Accepted: 06/26/2018] [Indexed: 12/25/2022] Open
Abstract
The intra-tumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. While the existing methods for studying tumor heterogeneity only analyze variant allele frequency (VAF), the genotype of variant is also informative for inferring subclones, which can be detected by long reads or paired-end reads. We developed GenoClone to integrate VAF with the genotype of variant innovatively, so it showed superior performance of inferring the number of subclones, estimating the fractions of subclones and identifying somatic single-nucleotide variants composition of subclones. When GenoClone was applied to 389 TCGA breast cancer samples, it revealed extensive intra-tumor heterogeneity. We further found that a few somatic mutations were relevant to the late stage of tumor evolution, including the ones at the oncogene PIK3CA and the tumor suppress gene TP53. Moreover, 52 subclones that were identified from 167 samples shared high similarity of somatic mutations, which were clustered into three groups with the sizes of 24, 14 and 14. It is helpful for understanding the development of breast cancer in certain subgroups of people and the drug development for population level. Furthermore, GenoClone also identified the tumor heterogeneity in different aliquots of the same samples. The implementation of GenoClone is available at http://www.healthcare.uiowa.edu/labs/au/GenoClone/.
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Affiliation(s)
- Meng Zou
- School of Mathematics and Statistics, Huazhong University of Science and Technology
| | - Rui Jin
- Department of Statistics, University of Iowa
| | - Kin Fai Au
- School of Mathematics and Statistics, Huazhong University of Science and Technology.,Department of Biomedical Informatics, Ohio State University
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Jiao R, Xu F, Huang X, Li H, Liu W, Cao H, Zang L, Li Z, Hua H, Li D. Antiproliferative chromone derivatives induce K562 cell death through endogenous and exogenous pathways. J Enzyme Inhib Med Chem 2020; 35:759-772. [PMID: 32183548 PMCID: PMC7144234 DOI: 10.1080/14756366.2020.1740696] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.
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Affiliation(s)
- Runwei Jiao
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Fanxing Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Xiaofang Huang
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Haonan Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Weiwei Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Hao Cao
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Linghe Zang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Zhanlin Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
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Wang Y, Qiu W, Liu N, Sun L, Liu Z, Wang S, Wang P, Liu S, Lv J. Forkhead box K1 regulates the malignant behavior of gastric cancer by inhibiting autophagy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:107. [PMID: 32175400 DOI: 10.21037/atm.2019.12.123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Forkhead box K1 (FOXK1) is a transcription factor that contributes to cancer development, but it is unclear how FOXK1 regulates the proliferation and migration of gastric cancer (GC) cells. The purpose of this study was to investigate the clinical significance, biological function, and molecular mechanisms of FOXK1 in GC. Methods We conducted bioinformatics assays and western blotting to assess FOXK1 expression. Then, we performed immunohistochemistry (IHC) with tissue microarrays (TMAs) to assess FOXK1 expression in order to identify an association between FOXK1 expression levels and clinical parameters. We used 5-ethynyl-2'-deoxyuridine (EdU), wound healing and Transwell assays to determine whether FOXK1 promotes malignant behaviors in GC. Furthermore, immunofluorescence staining, transmission electron microscopy and western blotting were used to verify an association between FOXK1 and autophagy. Results We observed high levels of FOXK1 expression in GC tissues, which were associated with the degree of malignancy in GC. FOXK1 promotes the malignant behavior of GC by regulating autophagy via activation of the class I phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and inhibition of the expression of class III PI3K. Conclusions These findings provide a new target for the comprehensive treatment of GC by highlighting the relationship between FOXK1 and malignant behaviors in GC.
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Affiliation(s)
- Yixuan Wang
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Wensheng Qiu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Ning Liu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Libin Sun
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Zhao Liu
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Shasha Wang
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Peng Wang
- Department of Oncology, Weifang Yidu Central Hospital, Qingzhou 262500, China
| | - Shihai Liu
- Central Laboratory, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Jing Lv
- Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
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Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells. Cancers (Basel) 2020; 12:cancers12020395. [PMID: 32046305 PMCID: PMC7072444 DOI: 10.3390/cancers12020395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/31/2020] [Accepted: 02/01/2020] [Indexed: 11/17/2022] Open
Abstract
Lesions with driver mutations, including atypical nevi and seborrheic keratoses, are very common in dermatology, and are prone to senescence. The molecular events that prevent senescent lesions from becoming malignant are not well understood. We have developed a model of vascular proliferation using a temperature-sensitive, large T antigen and oncogenic HRas. By elevating the temperature to 39 °C, we can turn off large T antigen and study the molecular events in cells with the Ras driver mutation. To assess the signaling events associated with the switch from a proliferative to a nonproliferative state in the constant presence of a driver oncogene, SVR cells were cultivated for 24 and 48 h and compared with SVR cells at 37 °C. Cells were evaluated by Western Blot (WB) gene chip microarray (GC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Upon evaluation, a novel phenotype was observed in endothelial cells after switching off the large T antigen. This phenotype was characterized by Notch activation, downregulation of p38 phosphorylation, downregulation of the master immune switch IRF7, and downregulation of hnRNP A0. Switching off proliferative signaling may result in immune privilege and Notch activation, which may account, in part, for the survival of common skin lesions.
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Ghoneum A, Abdulfattah AY, Said N. Targeting the PI3K/AKT/mTOR/NFκB Axis in Ovarian Cancer. JOURNAL OF CELLULAR IMMUNOLOGY 2020; 2:68-73. [PMID: 32395722 PMCID: PMC7213295 DOI: 10.33696/immunology.1.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ovarian cancer stands as the most lethal gynecologic malignancy and remains the fifth most common gynecologic cancer. Poor prognosis and low five-year survival rate are attributed to nonspecific symptoms at early phases along with a lack of effective treatment at advanced stages. It is thus paramount, that ovarian carcinoma be viewed through several lenses in order to gain a thorough comprehension of its molecular pathogenesis, epidemiology, histological subtypes, hereditary factors, diagnostic approaches, and methods of treatment. Above all, it is crucial to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This short communication seeks to underscore several important aspects of the PI3K/AKT/mTOR/NFκB pathway in the context of ovarian cancer and discuss recent advances in targeting this pathway.
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Affiliation(s)
- Alia Ghoneum
- Department of Cancer Biology, Wake Forest University School of Medicine, and Comprehensive Cancer Center, Winston Salem, NC 27157, USA
| | - Ammar Yasser Abdulfattah
- Department of Cancer Biology, Wake Forest University School of Medicine, and Comprehensive Cancer Center, Winston Salem, NC 27157, USA
| | - Neveen Said
- Department of Cancer Biology, Wake Forest University School of Medicine, and Comprehensive Cancer Center, Winston Salem, NC 27157, USA
- Department of Pathology, Wake Forest University School of Medicine, and Comprehensive Cancer Center, Winston Salem, NC 27157, USA
- Department of Urology, Wake Forest University School of Medicine, and Comprehensive Cancer Center, Winston Salem, NC 27157, USA
- Wake Forest Baptist Health Sciences, Winston Salem, NC 27157, USA
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PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis. Cancers (Basel) 2019; 12:cancers12010093. [PMID: 31905960 PMCID: PMC7017171 DOI: 10.3390/cancers12010093] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/18/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023] Open
Abstract
Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.
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Kobayashi Y, Lim SO, Yamaguchi H. Oncogenic signaling pathways associated with immune evasion and resistance to immune checkpoint inhibitors in cancer. Semin Cancer Biol 2019; 65:51-64. [PMID: 31874279 DOI: 10.1016/j.semcancer.2019.11.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/03/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs) are novel class of anti-cancer drugs that exhibit significant therapeutic effects even in patients with advanced-stage cancer. However, the efficacy of ICIs is limited due to resistance. Therefore, appropriate biomarkers to select patients who are likely to respond to these drugs as well as combination therapy to overcome the resistance are urgently necessary. Cancer is caused by various genetic alterations that lead to abnormalities in oncogenic signaling pathways. The aberrant oncogenic signaling pathways serve as not only prognostic and predictive biomarkers, but also targets for molecularly targeted therapy. Growing evidence shows that the aberrant oncogenic signaling pathways in cancer cells facilitate the resistance to ICIs by modulating the regulation of immune checkpoint and cancer immune surveillance. Indeed, it has been demonstrated that some molecular targeted therapies significantly improve the efficacy of ICIs in preclinical and clinical studies. In this review, we highlighted several oncogenic signaling pathways including receptor tyrosine kinases (RTKs), MAPK, PI3K-AKT-mTOR, JAK-STAT, Hippo, and Wnt pathways, and summarized the recent findings of the mechanisms underlying the regulation of cancer immunity and the ICI resistance induced by these aberrant oncogenic signaling pathways in cancer cells. Moreover, we discussed potential combination therapies with ICIs and molecularly targeted drugs to overcome the resistance and increase the efficacy of ICIs.
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Affiliation(s)
- Yoshie Kobayashi
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA
| | - Hirohito Yamaguchi
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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You I, Erickson EC, Donovan KA, Eleuteri NA, Fischer ES, Gray NS, Toker A. Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling. Cell Chem Biol 2019; 27:66-73.e7. [PMID: 31859249 DOI: 10.1016/j.chembiol.2019.11.014] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/28/2019] [Accepted: 11/25/2019] [Indexed: 11/17/2022]
Abstract
The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small-molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation.
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Affiliation(s)
- Inchul You
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA
| | - Emily C Erickson
- Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Katherine A Donovan
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA
| | - Nicholas A Eleuteri
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Eric S Fischer
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA
| | - Nathanael S Gray
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
| | - Alex Toker
- Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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MiR-337-3p suppresses proliferation of epithelial ovarian cancer by targeting PIK3CA and PIK3CB. Cancer Lett 2019; 469:54-67. [PMID: 31629932 DOI: 10.1016/j.canlet.2019.10.021] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 12/19/2022]
Abstract
Epithelial ovarian cancer (EOC) is responsible for nearly 140,000 deaths worldwide each year. MicroRNAs play critical roles in cancer development and progression. The function of microRNA miR-337-3p has been described in various cancers. However, the biological role of miR-337-3p and its molecular mechanisms underlying EOC initiation and progression have not been reported. Here, we reported that the expression of miR-337-3p is down-regulated in EOC tissues and low expression of miR-337-3p is correlated with advanced pathological grade for patients. Ectopic expression of miR-337-3p inhibited proliferation and induced apoptosis and cell cycle arrest in G0/G1 phase of EOC cells. PIK3CA and PIK3CB were revealed to be direct targets of miR-337-3p for reducing the activation of PI3K/AKT signaling pathway. PIK3CA and PIK3CB were discovered to affect cell proliferation of EOC cells in combination, and only when overexpressed simultaneously in miR-337-3p-expressing cells, could fully restore cell proliferation. In vivo investigation confirmed that miR-337-3p is a tumor suppressor that control expression of PIK3CA and PIK3CB encoded protein: p110α and p110β. Altogether, our results demonstrate that miR-337-3p is a tumor suppressor in EOC that inhibits the expression of PIK3CA and PIK3CB.
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Zhang L, Zhou Q, Qiu Q, Hou L, Wu M, Li J, Li X, Lu B, Cheng X, Liu P, Lu W, Lu Y. CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer. Mol Cancer 2019; 18:144. [PMID: 31623606 PMCID: PMC6796346 DOI: 10.1186/s12943-019-1080-5] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 09/25/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive. METHODS RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings. RESULTS CircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial-mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells. CONCLUSIONS Our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.
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Affiliation(s)
- Lei Zhang
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Qing Zhou
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiongzi Qiu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Ling Hou
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China
| | - Mengting Wu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Jia Li
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xufan Li
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bingjian Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China
| | - Xiaodong Cheng
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China
| | - Pengyuan Liu
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Physiology and Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Weiguo Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China
| | - Yan Lu
- Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, and Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310029, Zhejiang, China. .,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
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Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities. Nat Rev Urol 2019; 16:655-673. [PMID: 31602010 DOI: 10.1038/s41585-019-0233-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2019] [Indexed: 11/08/2022]
Abstract
Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10-15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β-EIF4EBP1, PI3K-AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.
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48
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Labrie M, Kendsersky ND, Ma H, Campbell L, Eng J, Chin K, Mills GB. Proteomics advances for precision therapy in ovarian cancer. Expert Rev Proteomics 2019; 16:841-850. [PMID: 31512530 PMCID: PMC6814571 DOI: 10.1080/14789450.2019.1666004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/06/2019] [Indexed: 10/26/2022]
Abstract
Introduction: Due to the relatively low mutation rate and high frequency of copy number variation, finding actionable genetic drivers of high-grade serous carcinoma (HGSC) is a challenging task. Furthermore, emerging studies show that genetic alterations are frequently poorly represented at the protein level adding a layer of complexity. With improvements in large-scale proteomic technologies, proteomics studies have the potential to provide robust analysis of the pathways driving high HGSC behavior. Areas covered: This review summarizes recent large-scale proteomics findings across adequately sized ovarian cancer sample sets. Key words combined with 'ovarian cancer' including 'proteomics', 'proteogenomic', 'reverse-phase protein array', 'mass spectrometry', and 'adaptive response', were used to search PubMed. Expert opinion: Proteomics analysis of HGSC as well as their adaptive responses to therapy can uncover new therapeutic liabilities, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is a pressing need to better understand how the genomic and epigenomic heterogeneity intrinsic to ovarian cancer is reflected at the protein level and how this information could be used to improve patient outcomes.
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Affiliation(s)
- Marilyne Labrie
- Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Nicholas D Kendsersky
- Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Hongli Ma
- Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Lydia Campbell
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
| | - Jennifer Eng
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
| | - Koei Chin
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
| | - Gordon B Mills
- Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
- Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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49
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Mendoza-Almanza G, Ortíz-Sánchez E, Rocha-Zavaleta L, Rivas-Santiago C, Esparza-Ibarra E, Olmos J. Cervical cancer stem cells and other leading factors associated with cervical cancer development. Oncol Lett 2019; 18:3423-3432. [PMID: 31516560 PMCID: PMC6733009 DOI: 10.3892/ol.2019.10718] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 06/06/2019] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer (CC) is one of the leading causes of cancer-associated mortalities in women from developing countries. Similar to other types of cancer, CC is considered to be a multifactorial disease, involving socioeconomic, cultural, immunological and epigenetic factors, as well as persistent human papilloma virus (HPV) infection. It has been well established that cancer stem cells (CSCs) play an important role in defining tumor size, the speed of development and the level of regression following treatment; therefore, CSCs are associated with a poor prognosis. CSCs have been detected in many types of cancer, including leukemia, pancreatic, colon, esophagus, liver, prostate, breast, gastric and lung cancer. In cervical cancer, CSCs have been associated with resistance to normally used drugs such as cisplatin. The present review summarizes the strategies that high-risk HPV viruses (HPV-16 and HPV-18) have developed to transform normal epithelial cells into cancer cells, as well as the cellular pathways and studies associated with the identification of cervical cancer stem cell biomarkers. In this sense, the present review provides state of the art information regarding CC development.
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Affiliation(s)
- Gretel Mendoza-Almanza
- National Council for Science and Technology, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | | | - Leticia Rocha-Zavaleta
- Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - César Rivas-Santiago
- National Council for Science and Technology, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | - Edgar Esparza-Ibarra
- Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98060, Mexico
| | - Jorge Olmos
- Department of Marine Biotechnology, Center for Scientific Research and Higher Education, Ensenada 22860, Mexico
- Correspondence to: Dr Jorge Olmos, Department of Marine Biotechnology, Center for Scientific Research and Higher Education, 3918 Carretera Ensenada-Tijuana, Ensenada 22860, Mexico, E-mail:
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50
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Kutahyalioglu M, Nguyen HT, Kwatampora L, Clarke C, Silva A, Ibrahim E, Waguespack SG, Cabanillas ME, Jimenez C, Hu MI, Sherman SI, Kopetz S, Broaddus R, Dadu R, Wanland K, Williams M, Zafereo M, Perrier N, Busaidy NL. Genetic profiling as a clinical tool in advanced parathyroid carcinoma. J Cancer Res Clin Oncol 2019; 145:1977-1986. [PMID: 31309300 DOI: 10.1007/s00432-019-02945-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022]
Abstract
CONTEXT Parathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy. OBJECTIVE To evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels. DESIGN All patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel. SETTING The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. PATIENTS OR OTHER PARTICIPANTS 11 patients with advanced PC were selected to undergo molecular testing. MAIN OUTCOME MEASURE(S) Genetic profiles of advanced PC. RESULTS Among the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3 K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients. CONCLUSIONS Mutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.
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Affiliation(s)
- Merve Kutahyalioglu
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Ha T Nguyen
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Lily Kwatampora
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Callisia Clarke
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Angelica Silva
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eiman Ibrahim
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Maria E Cabanillas
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Mimi I Hu
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Steven I Sherman
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Russell Broaddus
- Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ramona Dadu
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Kacey Wanland
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA
| | - Michelle Williams
- Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Zafereo
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nancy Perrier
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naifa L Busaidy
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street Unit 1461, Houston, TX, 77030, USA.
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