Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth

Cancer Cell. 2011 Jun 14;19(6):792-804. doi: 10.1016/j.ccr.2011.05.006. Epub 2011 May 27.

Abstract

Alteration of the PTEN/PI3K pathway is associated with late-stage and castrate-resistant prostate cancer (CRPC). However, how PTEN loss is involved in CRPC development is not clear. Here, we show that castration-resistant growth is an intrinsic property of Pten null prostate cancer (CaP) cells, independent of cancer development stage. PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of Ar in the epithelium promotes the proliferation of Pten null cancer cells, at least in part, by downregulating the androgen-responsive gene Fkbp5 and preventing PHLPP-mediated AKT inhibition. Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development, with potentially important implications for CaP etiology and therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Early Growth Response Protein 1 / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Male
  • Mice
  • Nuclear Proteins / physiology
  • Orchiectomy*
  • PTEN Phosphohydrolase / physiology*
  • Phosphoprotein Phosphatases / physiology
  • Phosphorylation
  • Polycomb Repressive Complex 2
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / prevention & control
  • Prostatic Neoplasms / therapy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Receptors, Androgen / physiology
  • Tacrolimus Binding Proteins / physiology

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • Receptors, Androgen
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • Proto-Oncogene Proteins c-akt
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5