Regulation of survivin expression by IGF-1/mTOR signaling

V. Vaira, C. W. Lee, H. L. Goel, S. Bosari, L. R. Languino, D. C. Altieri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2678-2684
Number of pages7
JournalOncogene
Volume26
Issue number19
DOIs
Publication statusPublished - Apr 26 2007

Keywords

  • IGF-1
  • mTOR
  • Prostate cancer
  • Rapamycin
  • Survivin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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