Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells bv IκB kinase α
Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells bv IκB kinase α
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DOI：
10.1158/0008-5472.can-07-1232
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Baldwin, Albert S.
中科院分区：
文献类型：
--
作者：
Dan, Han C.;Adli, Mazhar;Baldwin, Albert S.
哺乳动物雷帕霉素靶点 (mTOR) 是细胞生长、存活和能量代谢的介质，至少部分通过其调节 mRNA 翻译的能力实现。 mTOR 在生长因子、胰岛素和与癌蛋白表达或肿瘤抑制蛋白 PTEN 缺失相关的 Akt 依赖性信号传导下游被激活。在这方面，mTOR 活性与癌细胞的生长和存活相关。在这里，我们探索了与核因子 kappa B 激活相关的 I kappa B 激酶 (IKK) 通路在控制 mTOR 活性中的作用。实验表明，IKK α 控制 Akt 活性、PTEN 缺失的前列腺癌细胞中的 mTOR 激酶活性，而 IKK β 的参与较少。在这些细胞中，IKK α 作为 TORC1 复合物的一部分，以 Akt 依赖性方式与 mTOR 结合。此外，IKK α 是有效诱导组成型活性 Akt 表达下游 mTOR 活性所必需的。结果表明 IKK α 在控制具有组成型 Akt 活性的癌细胞中 mTOR 功能方面具有新作用。
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-kappa B 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, IKK alpha 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.