Abstract 4370: Arsenite stabilizes HIF-1α protein through p85α-mediated upregulation of inducible Hsp70 protein expression

Abstract

Abstract Arsenite has long been known as a human carcinogen. The hypoxia-inducible factor-1 (HIF-1) is an important transcription factor upon hypoxia and other stresses, which is proved to be associated with the pathogenesis of several cancers. Although hypoxia-inducible factor-1α (HIF-1α) has been reported to be activated by arsenite both in vivo and in vitro, the detailed molecular mechanisms leading to HIF-1α expression and activation due to arsenite exposure have not been well understood. In the present study, we found that arsenite is able to induce HIF-1α protein accumulation in both mouse epidermal Cl41 cells and mouse embryonic fibroblasts (MEFs). Knockout of p85α in MEFs (p85α−/−) led to the deficiency of HIF-1α protein accumulation induced by arsenite exposure, suggesting that p85α is crucial for arsenite-induced stabilization of HIF-1α protein. At the same time, our studies also show that p85a exhibited an inhibition of HIF-1α protein degradation via PI-3K/Akt-dependent pathway in cellular response to arsenite exposure. Our further studies revealed that arsenite exposure was able to induce inducible Hsp70 expression, and the deficiency of HIF-1α protein in p85α−/− MEF cells could be restored by introduction of inducible Hsp70 into p85α−/− MEF (p85α−/− (Hsp70)). Moreover, our results also indicated that p85α is crucial for arsenite-induced activation of heat shock transcription factor 1 (HSF-1), which is responsible for the transcription of inducible Hsp70. The transcriptional up-regulation of hsp70 by activated PI-3K/Akt pathway is strictly mediated by heat shock transcription factor-1 (HSF-1). Taken together, our studies demonstrated that p85α-mediated HIF-1α stabilization due to arsenite exposure is specific through p85α mediation of HSF-1 activation and subsequently transcriptional up-regulation of the inducible Hsp70. During this course, p85 regulated inducible Hsp70 expression transcription through PI-3K/Akt/HSF-1 pathway upon arsenite exposure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4370.