Abstract B34: IKKalpha regulation of mTORC1 and modulation of prostate tumorigenesis through phosphorylation of mTOR

Abstract

Abstract The mammalian target of rapamycin (mTOR) is a critical mediator of cell growth, cell proliferation, survival, and energy metabolism. 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 activity in Akt-active, PTEN-null prostate cancer cells by directly phosphorylation of mTOR at Serine 1415. In these cells, IKK alpha associates with mTORC1 and weaken the association between mTOR and Raptor, an important component of mTORC1, to increase mTORC1 kinase activity by phosphorylation in an Akt-dependent manner. Additionally, IKKalpha phosphorylation of mTOR is required for efficient induction of cell proliferation downstream of constitutively active Akt in these cells. The results indicate a novel role for IKKalpha in controlling mTOR function in protate cancer cells with loss of PTEN and constitutive Akt activity. Citation Format: Hancai Dan, Albert S. Baldwin. IKKalpha regulation of mTORC1 and modulation of prostate tumorigenesis through phosphorylation of mTOR [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B34.