Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-deficient Prostate Cancer

Cancer Cell. 2011 May 17;19(5):575-86. doi: 10.1016/j.ccr.2011.04.008.

Abstract

Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.

Publication types

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

MeSH terms

  • Androgen Antagonists / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Nuclear Proteins / metabolism
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / metabolism
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism*
  • Signal Transduction* / drug effects
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Androgen Antagonists
  • Myc protein, mouse
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • Phosphatidylinositol 3-Kinase
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse

Associated data

  • GEO/GSE24691