Abstract 4079: Control of survivin expression by IGF-I in prostate epithelial cells.

Survivin, a unique member of the inhibitor of apoptosis (IAP) proteins, is overexpressed in numerous cancers through poorly defined mechanisms. We show that insulin-like growth factor-I (IGF-I), which is implicated in the etiology of prostate cancer, induces the expression of Survivin in a variety of pre-neoplastic and malignant prostate cell lines. Using the pre-neoplastic NRP-152 rat prostate cell line as a model, we showed that silencing Survivin by lentiviral-mediated shRNA represses IGF-I-stimulated cell growth, suggesting that the induction of Survivin is critical to this growth response. Moreover, we show that IGF-I induces the expression of Survivin through a transcriptional mechanism that is mediated in part by the PI3K/Akt/mTORC1 pathway. The CDE and CHR response elements in the proximal region of the Survivin promoter are decisive for this IGF-I response. TGF-β signaling antagonists similarly induced this promoter activity and rendered cells refractory to further promoter activation by IGF-I. Suppression of TGF-β signaling, either by TGF-β receptor kinase inhibitors or by silencing Smads 2 and 3, induced Survivin expression and promoted cell growth similar to that induced by IGF-I. TGF-β receptor antagonists also rescued cells from down-regulation of Survivin expression and growth suppression by pharmacological inhibitors of PI3K, Akt, MEK and mTORC1. Sh-RNA gene silencing studies suggest that mTORC1 induces while mTORC2 represses the expression of Survivin. We conclude that IGF-I signaling through a PI3K/Akt/mTORC1-dependent mechanism elevates expression of Survivin and promotes growth of prostate epithelial cells by suppressing Smad-dependent autocrine TGF-β signaling. Citation Format: David Danielpour, Kyung Song, Eswar Shankar, Jiayi Yang, Kara L. Bane. Control of survivin expression by IGF-I in prostate epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2013-4079