Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation

Ross S. Liao, Shihong Ma, Lu Miao, Rui Li, Yi Yin, Ganesh V. Raj

Research output: Contribution to journalReview article

36 Scopus citations

Abstract

Androgen receptor (AR)-mediated signaling is necessary for prostate cancer cell proliferation and an important target for therapeutic drug development. Canonically, AR signals through a genomic or transcriptional pathway, involving the translocation of androgen-bound AR to the nucleus, its binding to cognate androgen response elements on promoter, with ensuing modulation of target gene expression, leading to cell proliferation. However, prostate cancer cells can show dose-dependent proliferation responses to androgen within minutes, without the need for genomic AR signaling. This proliferation response known as the non-genomic AR signaling is mediated by cytoplasmic AR, which facilitates the activation of kinase-signaling cascades, including the Ras-Raf-1, phosphatidyl-inositol 3-kinase (PI3K)/Akt and protein kinase C (PKC), which in turn converge on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation, leading to cell proliferation. Further, since activated ERK may also phosphorylate AR and its coactivators, the non-genomic AR signaling may enhance AR genomic activity. Non-genomic AR signaling may occur in an ERK-independent manner, via activation of mammalian target of rapamycin (mTOR) pathway, or modulation of intracellular Ca2+ concentration through plasma membrane G protein-coupled receptors (GPCRs). These data suggest that therapeutic strategies aimed at preventing AR nuclear translocation and genomic AR signaling alone may not completely abrogate AR signaling. Thus, elucidation of mechanisms that underlie non-genomic AR signaling may identify potential mechanisms of resistance to current anti-androgens and help developing novel therapies that abolish all AR signaling in prostate cancer.

Original languageEnglish (US)
Pages (from-to)187-196
Number of pages10
JournalTranslational Andrology and Urology
Volume2
Issue number3
DOIs
StatePublished - Sep 2013

Keywords

  • Androgen receptor (AR)
  • Cell proliferation
  • ERK MAP kinases
  • Non-genomic signaling
  • Prostate cancer

ASJC Scopus subject areas

  • Reproductive Medicine
  • Urology

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