Abstract 2694: Receptor-interacting protein kinase 2 promotes prostate cancer progression by activating the MAX:MYC pathway

Background: Prostate Cancer (PCa) is the most common non-skin cancer among American man. Currently, major challenges in the clinical management of PCa include 1) a lack of biomarkers that can reliably distinguish aggressive from indolent PCa and 2) a shortage of therapeutic strategies that can prevent or suppress the progression of PCa into aggressive PCa. Methods: Label-free quantitative proteomics was performed on three widely used PCa cell lines with different levels of aggressiveness (i.e., LNCaP, DU145 and PC3). Upstream regulator analysis and network modeling were conducted to identify candidate key promoters of PCa aggressiveness. The levels of gene amplification, mRNA expression, and protein expression of a key candidate promoter, receptor-interacting protein kinase 2 (RIPK2), were compared by analyzing publicly accessible PCa genomic and transcriptomic datasets and by immunohistochemistry (IHC) staining of PCa tissue microarrays (TMA). Cell proliferation and invasion assays were performed to compare PC3 cells with or without CRISPR/Cas9 knock-out of RIPK2. Quantitative proteomics and bioinformatics analysis were conducted to identify the underlying mechanisms, followed by validation via western blotting, quantitative real-time PCR (qRT-PCR) and in vitro functional assays. Results: Quantitative proteomics analysis of the three PCa cell lines identified over 6,500 proteins, among which 341 are significantly (adjusted p-value Conclusion: Taken together, our data elucidate that RIPK29s amplification and overexpression in PCa cells may activate the MAX:MYC-EIF2 signaling axis and thus in turn promote PCa cell proliferation and invasion. The aberrant activation of the RIPK2-MAX:MYC-EIF2 pathway may serve as a valuable biomarker and novel drug target of PCa progression. Citation Format: Yiwu Yan, Bo Zhou, Xiaopu Yuan, Michael E. Doche, Zhaoxuan Ma, Colm Morrissey, Arkadiusz Gertych, Sungyong You, Beatrice Knudsen, Michael R. Freeman, Wei Yang. Receptor-interacting protein kinase 2 promotes prostate cancer progression by activating the MAX:MYC pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2694.