Regulation of sensitivity of tumor cells to antitubulin drugs by Cdk1-TAZ signalling

Oncotarget. 2015 Sep 8;6(26):21906-17. doi: 10.18632/oncotarget.4259.

Abstract

Antitubulin drugs are commonly used for the treatment of numerous cancers. However, either the intrinsic or acquired resistances of patients to these drugs result in the failure of the treatment and high mortality of cancers. Therefore, identifying genes or signalling pathways involved in antitubulin drug resistances is critical for future successful treatment of cancers.TAZ (Transcriptional coactivator with PDZ-binding motif), which is a core component of the Hippo pathway, is overexpressed in various cancers. We have recently shown that high levels of TAZ in cancer cells result in Taxol resistance through up-regulation of downstream targets Cyr61 and CTGF. However, how TAZ is regulated in response to Taxol is largely unknown. In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. Phosphorylation-mimicking TAZ mutant was unstable, and therefore abolished TAZ-induced antitubulin drug resistances. This study provides first evidence that Cdk1 is a novel kinase phosphorylating and regulating TAZ stability and suggests that Cdk1-TAZ signalling is a critical regulator of antitubulin drug response in cancer cells and may be a potential target for the treatment of antitubulin-drug resistant cancer patients.

Keywords: Cdk1; Hippo; TAZ (WWTR1); antitubulin drug; chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • CDC2 Protein Kinase
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Drug Resistance, Neoplasm
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Paclitaxel / pharmacology
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tubulin Modulators / pharmacology*
  • Ubiquitin / metabolism
  • Up-Regulation

Substances

  • Antineoplastic Agents
  • Transcription Factors
  • Tubulin Modulators
  • Ubiquitin
  • TAFAZZIN protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Proteasome Endopeptidase Complex
  • Paclitaxel