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Regulation of survivin expression by IGF-1/mTOR signaling

Oncogene volume 26, pages 2678–2684 (2007)Cite this article

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.

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Acknowledgements

We thank Drs J Blenis for providing p70S6K cDNA, and R Baserga for cells expressing wild type and mutant IGF-IR. This work was supported by NIH grants CA109874 (LRL), CA90917, CA78810 and HL54131 (DCA) and DOD-PCRP DAMD PC040221 (LRL).

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Authors and Affiliations

  1. Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA

    V Vaira, C W Lee, H L Goel, L R Languino & D C Altieri

  2. Department of Medicine, Division of Pathology, Surgery and Dentistry, University of Milan, AOS Paolo and Fondazione Ospedale Maggiore Policlinico, Regina Elena and Mangiagalli, Milan, Italy

    V Vaira & S Bosari

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  1. V Vaira
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Correspondence to D C Altieri.

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Vaira, V., Lee, C., Goel, H. et al. Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 26, 2678–2684 (2007). https://doi.org/10.1038/sj.onc.1210094

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