Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha

Cancer Res. 2007 Jul 1;67(13):6263-9. doi: 10.1158/0008-5472.CAN-07-1232.

Abstract

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the I kappa B kinase (IKK) pathway, associated with nuclear factor-kappaB activation, in controlling mTOR activity. The experiments show that IKK alpha controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKK beta. In these cells, IKK alpha associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKKalpha is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • Male
  • Mice
  • PTEN Phosphohydrolase / metabolism*
  • Phenotype
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Kinases / biosynthesis*
  • Protein Kinases / physiology*
  • RNA Interference
  • RNA, Messenger / metabolism
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism

Substances

  • CRTC1 protein, human
  • RNA, Messenger
  • Transcription Factors
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • I-kappa B Kinase
  • PTEN Phosphohydrolase