RIP1 Activates PI3K-Akt via a Dual Mechanism Involving NF-B–Mediated Inhibition of the mTOR-S6K-IRS1 Negative Feedback Loop and Down-regulation of PTEN

Departments of ¹Neurology, ²Radiology, ³Pathology, ⁴Neurosurgery, and ⁵Radiation Oncology and ⁶Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas; ⁷Department of Neurology and Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ⁸Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁹Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky

^* To whom correspondence should be addressed. E-mail: Amyn.Habib{at}UTSouthwestern.edu.

	Abstract

Therapeutic inhibition of mammalian target of rapamycin (mTOR) in cancer is complicated by the existence of a negative feedback loop linking mTOR to the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Thus, mTOR inhibition by rapamycin or TSC1/2 results in increased PI3K-Akt activation. The death domain kinase receptor interacting protein 1 (RIP1) plays a key role in nuclear factor-B (NF-B) activation and also activates the PI3K-Akt pathway through unknown mechanisms. RIP1 has recently been found to be overexpressed in glioblastoma multiforme, the most common adult primary malignant brain tumor, but not in grade II to III glioma. Our data suggest that RIP1 activates PI3K-Akt using dual mechanisms by removing the two major brakes on PI3K-Akt activity. First, increased expression of RIP1 activates PI3K-Akt by interrupting the mTOR negative feedback loop. However, unlike other signals that regulate mTOR activity without affecting its level, RIP1 negatively regulates mTOR transcription via a NF-B–dependent mechanism. The second mechanism used by RIP1 to activate PI3K-Akt is down-regulation of cellular PTEN levels, which appears to be independent of NF-B activation. The clinical relevance of these findings is highlighted by the demonstration that RIP1 levels correlate with activation of Akt in glioblastoma multiforme. Thus, our study shows that RIP1 regulates key components of the PTEN-PI3K-Akt-mTOR pathway and elucidates a novel negative regulation of mTOR signaling at the transcriptional level by the NF-B pathway. Our data suggest that the RIP1-NF-B status of tumors may influence response to treatments targeting the PTEN-PI3K-mTOR signaling axis. [Cancer Res 2009;69(10):4107–11]

Key Words: PI3K-Akt, mammalian target of rapamycin, receptor interacting protein, NF-B, negative feedback