Abstract 2196: Upregulation of survivin during immortalization is linked to repression of p16INK4a and confers resistance to oxidative stress

Survivin is an essential component of the chromosomal passenger complex and a member of the Inhibitor of Apoptosis (IAP) family. It is expressed at high levels in a large variety of malignancies, where it is implicated in cytoprotection and drug resistance. Nevertheless, the pathways that mediate the cytoprotective functions of survivin and the mechanisms underlying its upregulation in cancer have not been fully elucidated. Results from our past investigations revealed that survivin was upregulated during telomerase-mediated immortalization of human myofibroblasts (MRC-5) (1). Since the immortalization process is an essential step in human carcinogenesis, upregulation of survivin during immortalization may explain why survivin is abundant in virtually all cancers. The present study aimed to characterize the mechanism responsible for the upregulation of survivin during immortalization, and the functional consequences of its over expression in immortal cells. Results from whole genome expression analyses and qRT-PCR demonstrated that the upregulation of survivin during immortalization was paralleled by increased expression of the transcription factor E2F1. The chromatin immunoprecipitation (ChIP) assay confirmed that E2F1 directly interacted with the survivin gene (BIRC5) promoter in immortal cells. Moreover, it was shown that E2F1 binding to BIRC5 was corresponded with repression of tumor suppressor p16INK4a, an event that commonly occurs during immortalization and human tumorigenesis. Survivin and p16INK4a were also functionally linked by assays that showed either upregulation of survivin or repression of p16INK4a rendered telomerase-transduced MRC-5 cells resistant to oxidative stress. Conversely, siRNA-mediated down regulation of survivin activated caspases and enhanced the sensitivity of immortal MRC-5 cells to oxidative stress. Together these data show that repression of p16INK4a contributes to the upregulation of survivin, and thereby provides a survival advantage to cells that are subject to oxidative stress during immortalization. 1. Yuan et al., Oncogene (2009) 28, 2678-2689. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2196. doi:1538-7445.AM2012-2196