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Oncogene. 2007 Apr 26;26(19):2678-84. Epub 2006 Oct 30.

Regulation of survivin expression by IGF-1/mTOR signaling.

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  • 1Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605, USA, and AOS Paolo and Fondazione Ospedale Maggiore Policlinico, Regina Elena and Mangiagalli, Milan, Italy.

Abstract

Survivin is a dual regulator of cell proliferation and cell viability overexpressed in most human tumors. Although strategies to lower survivin levels have been pursued for rational cancer therapy, the molecular circuitries controlling survivin expression in tumors have not been completely elucidated. Here, we show that stimulation with insulin-like growth factor-1 (IGF-1) results in increased survivin expression in prostate cancer cells. This response is independent of de novo gene transcription, changes in mRNA expression or modifications of survivin protein stability. Instead, IGF-1 induced persistence and translation of a pool of survivin mRNA, in a reaction abolished by the mTOR (mammalian target of rapamycin) inhibitor, rapamycin. Forced expression of the mTOR target p70S6K1 reproduced the increase in survivin expression in prostate cancer cells, whereas acute ablation of endogenous p70S6K1 by small interfering RNA downregulated survivin levels. Rapamycin, alone or in combination with suboptimal concentrations of taxol reduced survivin protein levels, and decreased viability of prostate cancer cells. Therefore, IGF-1/mTOR signaling elevates survivin in prostate cancer cells via rapid changes in mRNA translation. Antagonists of this pathway may be beneficial to lower an antiapoptotic threshold maintained by survivin in prostate cancer.

PMID:
17072337
[PubMed - indexed for MEDLINE]
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