title: TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling.
abstract: Epithelial ovarian cancer (EOC) is the most deadly gynaecologic malignancy due to late onset of symptoms and propensity towards drug resistance. Epithelial-mesenchymal transition (EMT) has been linked to the development of chemoresistance in other cancers, yet little is known regarding its role in EOC. In this study, we sought to determine the role of the transcription factor TWIST1, a master regulator of EMT, on cisplatin resistance in an EOC model. We created two Ovcar8-derived cell lines that differed only in their TWIST1 expression. TWIST1 expression led to increased tumour engraftment in mice, as well as cisplatin resistance in vitro. RNA sequencing analysis revealed that TWIST1 expression resulted in upregulation of GAS6 and L1CAM and downregulation of HMGA2. Knockdown studies of these genes demonstrated that loss of GAS6 or L1CAM sensitized cells to cisplatin, but that loss of HMGA2 did not give rise to chemoresistance. TWIST1, in part via GAS6 and L1CAM, led to higher expression and activation of Akt upon cisplatin treatment, and inhibition of Akt activation sensitized cells to cisplatin. These results suggest TWIST1- and EMT-driven increase in Akt activation, and thus tumour cell proliferation, as a potential mechanism of drug resistance in EOC.
authors.affiliation: Department of Developmental and Stem Cell Biology, 1500 E. Duarte Road Duarte, CA 91010, USA.|Irell and Manella Graduate School of Biological Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Cai M
authors.initials: CM
authors.lastname: Roberts
authors.affiliation: Department of Developmental and Stem Cell Biology, 1500 E. Duarte Road Duarte, CA 91010, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Tran
authors.affiliation: Division of Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Pitruzzello
authors.affiliation: Department of Surgery, Division of Gynaecologic Oncology, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: California State University, Los Angeles, 5151 State University Drive, Los Angeles, CA 90032, USA.
authors.forename: Joana
authors.initials: J
authors.lastname: Loeza
authors.affiliation: Department of Surgery, Division of Gynaecologic Oncology, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Dellinger
authors.affiliation: Division of Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.affiliation: Department of Developmental and Stem Cell Biology, 1500 E. Duarte Road Duarte, CA 91010, USA.
authors.forename: Carlotta A
authors.initials: CA
authors.lastname: Glackin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D025743:HMGA2 Protein / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D002945:Cisplatin; D025743:HMGA2 Protein; D036341:Intercellular Signaling Peptides and Proteins; D039842:Neural Cell Adhesion Molecule L1; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051879:Twist-Related Protein 1; D000099255:Growth Arrest-Specific Protein 6; C103173:TWIST1 protein, human