Abstract 2113: Programmed cell death 4 (PDCD4) regulates apoptotic resistance of human gliomas

Abstract Glioblastoma multiforme (GBM) is the most prevalent form of tumors of the central nervous system with an average survival rate of less than one year. Given the location and characteristics of GBM only limited treatment options are available, thus understanding the mechanisms of GBM formation or progression may lead to the development of novel treatment options. Strikingly, a common feature of GBM is the loss of expression of the tumor suppressor programmed cell death gene 4 (PDCD4), which correlates with a poor prognosis. Through both transcriptional and translational regulation, PDCD4 has been shown to regulate many proteins within the cell, although the precise mechanism of target selection is not known. We have hypothesised that silencing of PDCD4 in glioblastomas leads to an altered expression of apoptosis-regulating proteins resulting in the suppression of apoptotic signals and enhanced chemo-resistance of glioblastomas. Indeed, we show that low levels of PDCD4 correlate with an increase in the anti-apoptotic XIAP and Bcl-xL proteins, and decrease in pro-apoptotic Apaf-1. Importantly, these proteins are regulated at the level of protein synthesis through the internal ribosome entry sites (IRESs) in the 5’ untranslated region (UTR) of their respective mRNAs. IRES elements allow for translation to occur through a cap-independent mechanism during times of cellular stress when global translation is attenuated. We further show that PDCD4 regulates the activity of Bcl-xL, XIAP and Apaf-1 IRES and is therefore an IRES specific translational regulator. We further dissect the signalling pathways that regulate PDCD4 levels and show that activation of S6K2 results in the proteolytic degradation of PDCD4 and concomitant upregulation of XIAP and Bcl-xL, and downregulation of Apaf-1 levels. Importantly, reintroduction of PDCD4 into glioblastoma cell lines results in a reduction in both XIAP and Bcl-xL protein levels and enhanced cell death. In summary, our work provides a novel role for PDCD4 as a translational regulator of XIAP, Bcl-xL and Apaf-1, as well as a mechanistic understanding into the regulation of PDCD4 expression. Our research offers insight into the biology of glioblastomas in the hopes that we can identify new pathways as novel targets for anticancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2113. doi:10.1158/1538-7445.AM2011-2113