Abstract 1066: ERK/RSK and JNK signaling cooperatively mediate oncogenic Ras-induced death receptor 5 expression through enhancing CHOP, Elk1 and c-Jun-dependent transcription

Abstract

Abstract Oncogenic mutation of Ras frequently occurs in many types of cancers and plays a critical role in cell transformation and oncogenesis. Interestingly, the oncogenic Ras has been documented to induce the expression of death receptor 5 (DR5), a pro-apoptotic death domain-containing cell surface receptor for TRAIL, through currently undefined mechanisms. The current study attempted to address the mechanisms by which the oncogenic Ras induces DR5 expression. Enforced expression of the oncogenic H-Ras or K-Ras (e.g., RasV12) increased DR5 promoter activity and DR5 expression. This was also accompanied by activation of both ERK/RSK and JNK signaling pathways as evidenced by increased levels of p-ERK, p-RSK, p-JNK and p-c-Jun as well as their downstream proteins, CHOP, Elk1 and c-Jun. Gene silencing-mediated inhibition of either ERK, RSK or JNK activation blocked RasV12-induced DR5 expression. Moreover, knockdown of CHOP, Elk1 or c-Jun abrogated RasV12-induced DR5 expression as well. These data collectively indicate that both ERK/RSK and JNK signaling pathways are required for RasV12-induced DR5 expression. Triple gene (CHOP, Elk1 and c-Jun) co-expressed resulted in the highest DR5 promoter transactivation and protein expression in comparison to single or double gene expression. Consistently, oligonucleotide pull-down assay could detect Elk1, CHOP and c-Jun proteins bound to the DR5 promoter in cells co-transfected with CHOP, Elk1 and c-Jun genes or transfected with Ras-V12 gene, indicating that these proteins together bind to the DR5 promoter region. Thus we suggest that these three proteins cooperatively participate in RasV12-induced DR5 expression by enhancing its transcription. Importantly, we found that RasV12-transformed human ovarian cells were more sensitive than their non-transformed counterparts to undergo TRAIL-induced apoptosis. In summary, this study demonstrated that oncogenic Ras induces DR5 expression through activation of both ERK/RSK and JNK signaling pathways and subsequent CHOP, Elk1 and c-Jun-mediated gene transactivation. Cancers with Ras mutation may be suitable for TRAIL-based cancer 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 1066. doi:10.1158/1538-7445.AM2011-1066