Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer

Yu Wang, Jeffrey I. Kreisberg, Paramita M Ghosh

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Prostate cancer is initially dependent on androgens for growth; hence, recurrent prostate is treated with androgen ablation which may result in progression to androgen independence characterized by a resistance to such therapy. Androgens bind to and activate the androgen receptor (AR), a member of the nuclear steroid receptor family of transcription factors, which regulates prostate cancer cell proliferation and survival in androgen-independent, as well as -dependent, tumors. Another pathway regulating proliferation and survival is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Here we analyze reports in the literature indicating that these two pathways cooperate to regulate prostate tumor development and progression. Studies show that AR transcriptional activity and expression are regulated by Akt. In addition, androgens regulate the Akt pathway by both genomic and non-genomic effects. This explains why prostate tumors subjected to androgen ablation experience an increase in Akt phosphorylation, and suggest that the tumor compensates for the loss of one pathway with another. Different modes of interaction between the two pathways, including direct interaction, or regulation via downstream intermediates, such as the wnt/GSK-3β/β-catenin pathway, NF-κB, and the FOXO family of transcription factors, will be discussed. In addition, we will discuss the role of Akt in the interaction of the AR with upstream regulators of Akt phosphorylation, such as receptor tyrosine kinases of the EGF and IGF-1 receptor families and the tumor suppressor PTEN.

Original languageEnglish (US)
Pages (from-to)591-604
Number of pages14
JournalCurrent Cancer Drug Targets
Volume7
Issue number6
DOIs
StatePublished - Sep 2007

Keywords

  • Akt
  • Androgen receptor
  • Hormone dependence
  • Prostate cancer

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Cancer Research

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