Abstract 3397: Rational targeting of protein translation for cancer treatments

Abstract

Abstract Deregulation of protein translation is associated with a growing number of human diseases including tumorigenesis. New anti cancer therapies targeting the protein translation regulator mammalian Target Of Rapamycin (mTOR) highlight the importance of this signaling pathway. However, feedback mechanisms that can compensate for this general protein translation pathway limit the clinical efficiency of this approach. New drugs that could rationally target protein translation in cancer cells are therefore needed. We have identified the heterogenous ribonucleoprotein A18 (hnRNP A18) as a new regulator of protein translation in cancer cells. hnRNP A18 is up regulated in several human tumors including prostate, breast, colon and as shown here in melanoma tumors. hnRNP A18 regulates protein translation of its targeted transcripts by binding to a specific RNA signature motif in their 3’UTRs. Our data indicate that the hypoxia mimetic agent CoCl2 increases hnRNP A18 protein levels in melanoma cells but not in normal melanocytes. In addition, down regulation of hnRNP A18 sensitizes melanoma cells to CoCl2 and Temozolimide. The functional significance of this effect was evaluated in a mouse xenograft model where hnRNP A18 down regulation reduced melanoma tumor growth by more than 70%. RNA immunoprecipitation assay indicate that hnRNP A18 binds to a number of transcripts associated with tumor growth including the Hypoxia Inducible Factor 1α (HIF-1α). Levels of hnRNP A18 also directly affect HIF-1α protein levels in response to CoCl2. Taken together these data indicate that hnRNP A18 is a new regulator of protein translation that could be targeted to develop new mechanism based therapy for the rational inhibition of protein translation in cancer cells. Citation Format: Elizabeth Chang, Duc Nguyen, Qingyuan Yang, France Carrier. Rational targeting of protein translation for cancer treatments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3397. doi:10.1158/1538-7445.AM2014-3397