title: Tetrathiomolybdate mediates cisplatin-induced p38 signaling and EGFR degradation and enhances response to cisplatin therapy in gynecologic cancers.
abstract: Cisplatin and its analogs are among the most widely used chemotherapeutic agents against various types of cancer. It is known that cisplatin can activate epidermal growth factor receptor (EGFR), which may provide a survival benefit in cancers. Tetrathiomolybdate (TM) is a potent anti-cancer and anti-angiogenic agent and has been investigated in a number of clinical trials for cancer. In this study, we explore the therapeutic potential of TM on cisplatin-mediated EGFR regulation. Our study shows that TM is not cytotoxic, but exerts an anti-proliferative effect in ECC-1 cells. However, TM treatment prior to cisplatin markedly improves cisplatin-induced cytotoxicity. TM suppressed cisplatin-induced activation of EGFR while potentiating activation of p38; the activation of p38 signaling appeared to promote cisplatin-induced EGFR degradation. These results are in contrast to what we saw when cells were co-treated with cisplatin plus an EGFR tyrosine kinase inhibitor, where receptor activation was inhibited but receptor degradation was also blocked. Our current study is in agreement with previous findings that TM may have a therapeutic benefit by inhibiting EGFR activation. We furthermore provide evidence that TM may provide an additional benefit by potentiating p38 activation following cisplatin treatment, which may in turn promote receptor degradation by cisplatin.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Kyu Kwang
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Han
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Ribeiro
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lokich
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School, Brown University, Providence, RI, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008982:Molybdenum / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000970:Antineoplastic Agents; C000606290:SOD1 protein, human; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin