Post-transcriptional regulation of the androgen receptor by Mammalian target of rapamycin

Cancer Res. 2005 Apr 1;65(7):2547-53. doi: 10.1158/0008-5472.CAN-04-3411.

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an ErbB1 ligand and prostate stromal growth factor, is an antagonist of androgen receptor (AR) function. In the LNCaP prostate cancer model, HB-EGF reduced AR protein levels and AR transactivation without affecting AR mRNA level or protein turnover. The signal to attenuate AR was mediated by the mammalian target of rapamycin, as shown by genetic and pharmacologic methods, and was independent of ErbB2/HER-2, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase pathways. Additional evidence suggests that AR protein levels are highly sensitive to regulation by cap-dependent mRNA translation. These findings reveal a novel mechanism for regulation of AR by a classic growth factor system and indicate that a rapamycin-sensitive post-transcriptional pathway can attenuate or possibly bypass AR-mediated signaling.

Publication types

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

MeSH terms

  • Androgen Receptor Antagonists
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Down-Regulation
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Protein Biosynthesis
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Androgen / physiology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection

Substances

  • Androgen Receptor Antagonists
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Androgen
  • Epidermal Growth Factor
  • Cycloheximide
  • Protein Kinases
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases