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

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