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Regulation of Mammalian Target of Rapamycin Activity in PTEN-Inactive Prostate Cancer Cells by IB Kinase

Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Requests for reprints: Albert S. Baldwin, Lineberger Comprehensive Cancer Center, CB7295, University of North Carolina, Chapel Hill, NC 27599. Phone: 919-966-3652; Fax: 919-966-0444; E-mail: abaldwin{at}med.unc.edu.

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 IB kinase (IKK) pathway, associated with nuclear factor-B activation, in controlling mTOR activity. The experiments show that IKK controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKKß. In these cells, IKK associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKK is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKK in controlling mTOR function in cancer cells with constitutive Akt activity. [Cancer Res 2007;67(13):6263–9]

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