Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β- catenin signaling in prostate cancer cells

Monica Ciarlo, Roberto Benelli, Ottavia Barbieri, Simona Minghelli, Paola Barboro, Cecilia Balbi, Nicoletta Ferrari

Research output: Contribution to journalArticlepeer-review

Abstract

Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and β-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and β-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.

Original languageEnglish
Pages (from-to)582-590
Number of pages9
JournalInternational Journal of Cancer
Volume131
Issue number3
DOIs
Publication statusPublished - Aug 1 2012

Keywords

  • β-catenin
  • AKT
  • androgen receptor
  • heterogeneous nuclear ribonucleoprotein K
  • neuroendocrine differentiation
  • prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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