Platinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism

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dc.contributor.authorLeung, D.
dc.contributor.authorPrice, Z.K.
dc.contributor.authorLokman, N.A.
dc.contributor.authorWang, W.
dc.contributor.authorGoonetilleke, L.
dc.contributor.authorKadife, E.
dc.contributor.authorOehler, M.K.
dc.contributor.authorRicciardelli, C.
dc.contributor.authorKannourakis, G.
dc.contributor.authorAhmed, N.
dc.date.issued2022
dc.description.abstractBackground: Epithelial ovarian cancer is the most lethal gynaecological cancer worldwide. Chemotherapy resistance represents a significant clinical challenge and is the main reason for poor ovarian cancer prognosis. We identified novel expression of markers related to epithelial mesenchymal transitions (EMT) in a carboplatin resistant ovarian cancer cell line by proteomics. This was validated in the platinum resistant versus sensitive parental cell lines, as well as platinum resistant versus sensitive human ovarian cancer patient samples. The prognostic significance of the different proteomics-identified marker proteins in prognosis prediction on survival as well as their correlative association and influence on immune cell infiltration was determined by public domain data bases. Methods: We explored the proteomic differences between carboplatin-sensitive OVCAR5 cells (parental) and their carboplatin-resistant counterpart, OVCAR5 CBPR cells. qPCR and western blots were performed to validate differentially expressed proteins at the mRNA and protein levels, respectively. Association of the identified proteins with epithelial–mesenchymal transition (EMT) prompted the investigation of cell motility. Cellular bioenergetics and proliferation were studied to delineate any biological adaptations that facilitate cancer progression. Expression of differentially expressed proteins was assessed in ovarian tumors obtained from platinum-sensitive (n = 15) versus platinum-resistant patients (n = 10), as well as matching tumors from patients at initial diagnosis and following relapse (n = 4). Kaplan–Meier plotter and Tumor Immune Estimation Resource (TIMER) databases were used to determine the prognostic significance and influence of the different proteomics-identified proteins on immune cell infiltration in the tumor microenvironment (TME). Results: Our proteomics study identified 2422 proteins in both cell lines. Of these, 18 proteins were upregulated and 14 were downregulated by ≥ twofold (p < 0.05) in OVCAR5 CBPR cells. Gene ontology enrichment analysis amongst upregulated proteins revealed an overrepresentation of biological processes consistent with EMT in the resistant cell line. Enhanced mRNA and/or protein expression of the identified EMT modulators including ITGA2, TGFBI, AKR1B1, ITGAV, ITGA1, GFPT2, FLNA and G6PD were confirmed in OVCAR5 CBPR cells compared to parental OVCAR5 cell line.Consistent with the altered EMT profile, the OVCAR5 CBPR cells demonstrated enhanced migration and reduced proliferation, glycolysis, and oxidative phosphorylation. The upregulation of G6PD, AKR1B1, ITGAV, and TGFβ1 in OVCAR5 CBPR cells was also identified in the tumors of platinum-resistant compared to platinum-sensitive high grade serous ovarian cancer (HGSOC) patients. Matching tumors of relapsed versus newly diagnosed HGSOC patients also showed enhanced expression of AKR1B1, ITGAV, TGFβ1 and G6PD protein in relapsed tumors. Among the identified proteins, significant enhanced expression of GFPT2, FLNA, TGFBI (CDGG1), ITGA2 predicted unfavorable prognosis in ovarian cancer patients. Further analysis suggested that the expression of TGFBI to correlate positively with the expression of identified and validated proteins such as GFPT2, FLNA, G6PD, ITGAV, ITGA1 and ITGA2; and with the infiltration of CD8+ T cells, macrophages, neutrophils, and dendritic cells in the TME. Conclusions: Our research demonstrates proteomic-based discovery of novel EMT-related markers with an altered metabolic profile in platinum-resistant versus sensitive ovarian cancer cell lines. The study also confirms the expression of selected identified markers in the tumors of platinum-resistant versus sensitive, and in matching relapsed versus newly diagnosed HGSOC patients. The study provides insights into the metabolic adaptation of EMT-induced carboplatin resistant cells that confers on them reduced proliferation to provide effective migratory advantage; and the role of some of these identified proteins in ovarian cancer prognosis. These observations warrant further investigation of these novel target proteins in platinum-resistant patients.
dc.description.statementofresponsibilityDilys Leung, Zoe K. Price, Noor A. Lokman, Wanqi Wang, Lizamarie Goonetilleke, Elif Kadife, Martin K. Oehler, Carmela Ricciardelli, George Kannourakis, and Nuzhat Ahmed
dc.identifier.citationJournal of Translational Medicine, 2022; 20(1):556-1-556-23
dc.identifier.doi10.1186/s12967-022-03776-y
dc.identifier.issn1479-5876
dc.identifier.issn1479-5876
dc.identifier.orcidPrice, Z.K. [0000-0001-5306-3468]
dc.identifier.orcidLokman, N.A. [0000-0002-2071-5308]
dc.identifier.orcidWang, W. [0000-0003-0900-0712]
dc.identifier.orcidOehler, M.K. [0000-0002-2651-5913]
dc.identifier.orcidRicciardelli, C. [0000-0001-7415-1854]
dc.identifier.urihttps://hdl.handle.net/2440/145830
dc.language.isoen
dc.publisherBMC
dc.rights© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
dc.source.urihttps://doi.org/10.1186/s12967-022-03776-y
dc.subjectEpithelial–mesenchymal transition; Epithelial ovarian cancer; AKR1B1; ITGAV; TGFB1; Platinum-resistance
dc.subject.meshHumans
dc.subject.meshFemale
dc.subject.meshCarcinoma, Ovarian Epithelial
dc.subject.meshEpithelial-Mesenchymal Transition
dc.subject.meshCarboplatin
dc.subject.meshProteomics
dc.subject.meshCD8-Positive T-Lymphocytes
dc.subject.meshOvarian Neoplasms
dc.subject.meshPlatinum
dc.subject.meshRNA, Messenger
dc.subject.meshTumor Microenvironment
dc.subject.meshAldehyde Reductase
dc.subject.meshDrug Resistance, Neoplasm
dc.titlePlatinum-resistance in epithelial ovarian cancer: an interplay of epithelial–mesenchymal transition interlinked with reprogrammed metabolism
dc.typeJournal article
pubs.publication-statusPublished

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