Crosstalk between nuclear MET and SOX9/β-catenin correlates with castration-resistant prostate cancer. Academic Article uri icon

Overview

abstract

  • Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

publication date

  • August 6, 2014

Research

keywords

  • Prostate
  • Prostatic Neoplasms, Castration-Resistant
  • Proto-Oncogene Proteins c-met
  • SOX9 Transcription Factor
  • beta Catenin

Identity

PubMed Central ID

  • PMC4179634

Scopus Document Identifier

  • 84907678055

Digital Object Identifier (DOI)

  • 10.1016/j.molonc.2014.05.006

PubMed ID

  • 25099011

Additional Document Info

volume

  • 28

issue

  • 10