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Kumari S, Gupta S, Jamil A, Tabatabaei D, Karakashev S. Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy. J Cell Physiol 2025; 240:e31495. [PMID: 39676338 DOI: 10.1002/jcp.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.
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Affiliation(s)
- Sangeeta Kumari
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Shraddha Gupta
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Aisha Jamil
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Deyana Tabatabaei
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
| | - Sergey Karakashev
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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Chen LY, Shen YA, Chu LH, Su PH, Wang HC, Weng YC, Lin SF, Wen KC, Liew PL, Lai HC. Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor. Antioxidants (Basel) 2024; 13:735. [PMID: 38929174 PMCID: PMC11200674 DOI: 10.3390/antiox13060735] [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: 04/22/2024] [Revised: 06/04/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.
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Grants
- MOST 109-2314-B-038-052-MY3 Ministry of Science and Technology, Taiwan
- MOST 108-2314-B-038-096 Ministry of Science and Technology, Taiwan
- MOST 110-2314-B-038-060 Ministry of Science and Technology, Taiwan
- MOST 111-2314-B-038-108-MY3 Ministry of Science and Technology, Taiwan
- MOST 110- 471 2314-B-038-059 Ministry of Science and Technology, Taiwan
- MOST 110-2635-B-038-001 Ministry of Science and Technology, Taiwan
- MOST 109-2314-B-038-021-MY3 Ministry of Science and Technology, Taiwan
- 109TMU-SHH-20 Taipei Medical University-Shuang Ho Hospital, Taiwan
- TMU109-AE1-B22 Taipei Medical University, Taiwan
- MOST 109-2314-B-038-107-MY3 Ministry of Science and Technology, Taiwan
- MOST 111-2320-B-038-023-MY3 Ministry of Science and Technology, Taiwan
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Affiliation(s)
- Lin-Yu Chen
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (L.-Y.C.); (L.-H.C.); (K.-C.W.)
| | - Yao-An Shen
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ling-Hui Chu
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (L.-Y.C.); (L.-H.C.); (K.-C.W.)
| | - Po-Hsuan Su
- College of Health Technology, National Taipei University of Nursing and Health Sciences, Taipei 11219, Taiwan;
| | - Hui-Chen Wang
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yu-Chun Weng
- Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
| | - Shiou-Fu Lin
- Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
| | - Kuo-Chang Wen
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (L.-Y.C.); (L.-H.C.); (K.-C.W.)
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Phui-Ly Liew
- Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
| | - Hung-Cheng Lai
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (L.-Y.C.); (L.-H.C.); (K.-C.W.)
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
- Translational Epigenetics Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Sato M, Sato S, Shintani D, Hanaoka M, Ogasawara A, Miwa M, Yabuno A, Kurosaki A, Yoshida H, Fujiwara K, Hasegawa K. Clinical significance of metabolism-related genes and FAK activity in ovarian high-grade serous carcinoma. BMC Cancer 2022; 22:59. [PMID: 35027024 PMCID: PMC8756654 DOI: 10.1186/s12885-021-09148-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC). METHODS The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed ( https://portal.gdc.cancer.gov/ ). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant. RESULTS In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307). CONCLUSION In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.
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Affiliation(s)
- Masakazu Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
| | - Sho Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Daisuke Shintani
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Mieko Hanaoka
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Aiko Ogasawara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Maiko Miwa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Akira Yabuno
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Akira Kurosaki
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Hiroyuki Yoshida
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | | | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
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Xu X, Chen F, Zhang L, Liu L, Zhang C, Zhang Z, Li W. Exploring the mechanisms of anti-ovarian cancer of Hedyotis diffusa Willd and Scutellaria barbata D. Don through focal adhesion pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114343. [PMID: 34147618 DOI: 10.1016/j.jep.2021.114343] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/28/2021] [Accepted: 06/15/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hedyotis diffusa Willd and Scutellaria barbata D.Don (HD-SB) pairing were widely used as traditional medicine known for their anti-tumor effects. However, the inhibitory effect of HD-SB on ovarian cancer and its potential mechanisms were still not clear. AIM OF THE STUDY Our study identified the anti-tumor effect of HD-SB on ovarian cancer and analyzed the potential mechanisms by the network pharmacology and molecular docking method. MATERIALS AND METHODS The inhibitory effect of HD-SB combination on the growth and migration of ovarian cancer was detected by MTT and transwell assays. The effective ingredients of HD-SB and their potential targets were obtained from the Traditional Chinese Medicines for Systems Pharmacology Database (TCMSP), the GeneCards database, and the UniProt database. The relationships between active ingredients of HD-SB and potential targets or pathways of ovarian cancer were analyzed by String database, Cytoscape 3.7.2 software, and David 6.7 online database. The anti-ovarian cancer targets of HD-SB in the focal adhesion pathway were identified by RT-qPCR and molecular docking. RESULTS HD-SB combination significantly inhibited the proliferation and migration of ovarian cancer cells. We observed that the 1:2 ratio of HD-SB had the lowest IC50 value. 60 gene targets of 33 active ingredients in HD-SB were selected by pharmacokinetic parameters. The network pharmacological analysis showed that quercetin, luteolin, and baicalein might be the important anti-ovarian cancer ingredients in HD-SB, and the inhibitory effects of these three ingredients on the proliferation of ovarian cancer cells were verified respectively. Functional enrichment results suggested that HD-SB inhibited ovarian cancer growth and migration mainly through the focal adhesion pathway and the potential targets were EGFR, MAPK1, VEGFA, and PIK3CG. CONCLUSIONS HD-SB pairing significantly inhibited the proliferation and migration of ovarian cancer. Using network pharmacological methods and validation experiments, we found that HD-SB might, at least partially, inhibit ovarian cancer through the focal adhesion pathway. We believed that the HD-SB combination could be a potential therapeutic drug for the treatment of ovarian cancer patients.
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Affiliation(s)
- Xiao Xu
- Department of Biotechnology, Dalian Medical University, Dalian, China.
| | - Fenglin Chen
- Department of Biotechnology, Dalian Medical University, Dalian, China.
| | - Lin Zhang
- Academy of Integrative Medicine, Dalian Medical University, Dalian, 116044, Liaoning, China.
| | - Likun Liu
- Department of Biotechnology, Dalian Medical University, Dalian, China.
| | - Cuili Zhang
- Department of Biotechnology, Dalian Medical University, Dalian, China.
| | - Zhiwei Zhang
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, 116044, Liaoning, China.
| | - Weiling Li
- Department of Biotechnology, Dalian Medical University, Dalian, China.
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Subbannayya Y, Di Fiore R, Urru SAM, Calleja-Agius J. The Role of Omics Approaches to Characterize Molecular Mechanisms of Rare Ovarian Cancers: Recent Advances and Future Perspectives. Biomedicines 2021; 9:1481. [PMID: 34680597 PMCID: PMC8533212 DOI: 10.3390/biomedicines9101481] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/05/2021] [Accepted: 10/12/2021] [Indexed: 01/02/2023] Open
Abstract
Rare ovarian cancers are ovarian cancers with an annual incidence of less than 6 cases per 100,000 women. They generally have a poor prognosis due to being delayed diagnosis and treatment. Exploration of molecular mechanisms in these cancers has been challenging due to their rarity and research efforts being fragmented across the world. Omics approaches can provide detailed molecular snapshots of the underlying mechanisms of these cancers. Omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, can identify potential candidate biomarkers for diagnosis, prognosis, and screening of rare gynecological cancers and can aid in identifying therapeutic targets. The integration of multiple omics techniques using approaches such as proteogenomics can provide a detailed understanding of the molecular mechanisms of carcinogenesis and cancer progression. Further, omics approaches can provide clues towards developing immunotherapies, cancer recurrence, and drug resistance in tumors; and form a platform for personalized medicine. The current review focuses on the application of omics approaches and integrative biology to gain a better understanding of rare ovarian cancers.
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Affiliation(s)
- Yashwanth Subbannayya
- Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Riccardo Di Fiore
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
| | - Silvana Anna Maria Urru
- Hospital Pharmacy Unit, Trento General Hospital, Autonomous Province of Trento, 38122 Trento, Italy;
- Department of Chemistry and Pharmacy, School of Hospital Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
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Sansa A, Venegas MDP, Valero C, Pardo L, Avilés-Jurado FX, Terra X, Quer M, León X. The aspartate aminotransaminase/alanine aminotransaminase (De Ritis) ratio predicts sensitivity to radiotherapy in head and neck carcinoma patients. Head Neck 2021; 43:2091-2100. [PMID: 33675096 DOI: 10.1002/hed.26673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/27/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The aim of this study is to evaluate the relationship between the aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) ratio and local disease control in patients with head and neck squamous cell carcinomas (HNSCC) treated with radiotherapy/chemoradiotherapy. METHODS We calculated the pre-treatment AST/ALT ratio in 670 patients with HNSCC treated with radiotherapy (n = 309, 46.1%) or chemoradiotherapy (n = 361, 53.9%). RESULTS Five-year local recurrence-free survival for patients with a low AST/ALT ratio value (n = 529, 79.0%) was 75.0% (95% CI: 71.1-78.9), and for patients with a high value (n = 141, 21.0%) it was 53.4% (CI 95: 44.4-62.4) (p = 0.0001). In a multivariable analysis, patients with a high ratio had nearly twice the risk of having a local tumor recurrence (HR 1.97, 95% CI 1.42-2.75, p = 0.0001). CONCLUSION The AST/ALT ratio was independently associated with the risk of local recurrence in patients with HNSCC treated with radiotherapy or chemoradiotherapy.
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Affiliation(s)
- Aina Sansa
- Department of Otorhinolaryngology, Hospital Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - María Del Prado Venegas
- Department of Otorhinolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Cristina Valero
- Department of Otorhinolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Laura Pardo
- Department of Otorhinolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francesc-Xavier Avilés-Jurado
- Department of Otorhinolaryngology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), Spain
| | - Ximena Terra
- MoBioFood Research Group, Biochemistry and Biotechnology Department, Universitat Rovira i Virgili, Tarragona, Spain
| | - Miquel Quer
- Department of Otorhinolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Xavier León
- Department of Otorhinolaryngology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
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The Communication Between the PI3K/AKT/mTOR Pathway and Y-box Binding Protein-1 in Gynecological Cancer. Cancers (Basel) 2020; 12:cancers12010205. [PMID: 31947591 PMCID: PMC7017275 DOI: 10.3390/cancers12010205] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/04/2020] [Accepted: 01/10/2020] [Indexed: 12/19/2022] Open
Abstract
Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.
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Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells. MEDICINES 2018; 5:medicines5010016. [PMID: 29389895 PMCID: PMC5874581 DOI: 10.3390/medicines5010016] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/11/2018] [Accepted: 01/12/2018] [Indexed: 02/07/2023]
Abstract
Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS-OvCas; about 50% of these tumors displayed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes; somatic copy number alterations are frequent in these tumors and some of them are associated with prognosis; defective NOTCH, RAS/MEK, PI3K and FOXM1 pathway signaling is frequent. Other histological subtypes were characterized by a different mutational spectrum: LGS-OvCas have increased frequency of BRAF and RAS mutations; mucinous cancers have mutation in ARID1A, PIK3CA, PTEN, CTNNB1 and RAS. Intensive research was focused to characterize ovarian cancer stem cells, based on positivity for some markers, including CD133, CD44, CD117, CD24, EpCAM, LY6A, ALDH1. Ovarian cancer cells have an intrinsic plasticity, thus explaining that in a single tumor more than one cell subpopulation, may exhibit tumor-initiating capacity. The improvements in our understanding of the molecular and cellular basis of ovarian cancers should lead to more efficacious treatments.
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