Title: Abstract 3675: Farnesyltransferase inhibitor (FTI) disruption of Rheb/FKBP38 association leads to FKBP38-mediated inactivation of mTOR
Abstract: Abstract The activation of the Rheb (Ras homologue enriched in brain) / mTOR (mammalian target of rapamycin) pathway plays a central role in integrating growth factor, nutrient and energy signals and regulates cell growth (cell mass and size) and proliferation (cell number). Recently Rheb was found to activate mTOR by binding and antagonizing its endogenous inhibitor, FKBP38. However, it is not known whether inhibition of Rheb farnesylation by farnesyltransferase Inhibitors (FTIs) is sufficient to disrupt Rheb/FKBP38 interaction and leads to inactivation of mTOR. Here we demonstrate that FTI-2153 disrupts Rheb binding to FKBP38 allowing FKBP38 to bind and to inactivate mTOR. Furthermore, in human cancer cells, FTI-2153 also blocks IGF-1-stimulated Rheb/FKBP38 binding and promotes mTOR/FKBP38 binding. We further show that FTI-2153 inhibits Rheb-mediated activation of mTOR to phosphorylate S6 kinase, and that a geranylgeranylated mutant variant of Rheb that is as efficient as wild-type farnesylated Rheb at activating mTOR rescues cancer cells from FTI-induced inactivation of mTOR signaling, inhibition of anchorage-dependent and -independent tumor cell growth and induction of apoptosis. These results demonstrate that FTI-mediated disruption of the Rheb/FKBP38 interaction leads to inactivation of mTOR and is an effective approach to inhibiting tumor proliferation and survival and that inhibition of Rheb farnesylation mediates, at least in part, the anti-tumor effects of FTIs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3675.
Publication Year: 2010
Publication Date: 2010-04-01
Language: en
Type: article
Indexed In: ['crossref']
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