title: YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a Hippo-independent pathway.
abstract: Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston;
authors.forename: Yulei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston;
authors.forename: Prem
authors.initials: P
authors.lastname: Khanal
authors.affiliation: Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Savage
authors.affiliation: Centre for Biologics Research, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario;
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: She
authors.affiliation: Centre for Biologics Research, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario;
authors.forename: Terry D
authors.initials: TD
authors.lastname: Cyr
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston; yang@path.queensu.ca.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yang
mesh_terms: D000217:Acyltransferases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016203:CDC2 Protein Kinase; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D019926:Cyclin B; D009687:Nuclear Proteins; D014157:Transcription Factors; D014404:Tubulin; D050257:Tubulin Modulators; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases