MSACL 2019 EU Abstract

Characterizing the Novel Metastatic Regulator in CRPC-based on Quantitative Proteomics

Do Eun Kim, So Yeon Jeong, Ju Mi Jeon, Jong-Sup Bae, Sangkyu Lee
BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea

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Do Eun Kim (Presenter) College of Pharmacy, Kyungpook National University

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Conflict mitigation NOT REQUIRED.

INTRODUCTION: Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. In 2017, the American Cancer Society reported a large increase in the rate of new PCa cases, accounting for 57% of all new genital cancer cases. Among patients who develop advanced PCa, 80% suffer from bone metastasis, with a sharp drop in survival rate.

OBJECTIVES: Despite much effort, the details of the mechanisms underlying castration-resistant PCa (CRPC) remain unclear. SIRT5, an NAD+-dependent deacylase, is hypothesized to be a key regulator of various cancers, but compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied.

METHODS: Here we show significantly decreased levels of SIRT5 in PC-3M, a CRPC cell model with increased aggressiveness compared to the parental PC-3 cells, and we confirmed that downregulation of SIRT5 promoted cell migration and invasion. PC-3 and PC-3 SIRT5 KO cells were grown in SILAC media and normal RPMI media, respectively. Using quantitative proteomics analysis, we characterized the differentially expressed proteins (DEPs) between parental and SIRT5 KO PC-3 cells.

RESULTS: We identified 3,699 proteins and quantified 3,073 proteins through the MaxQuant database search program, including 26 down- and 24 up-regulated proteins, respectively. Among up-regulated proteins, we found a substantial increase in interleukin-1b (IL-1b) expression in SIRT5 KO cells, and the PI3K/AKT/NF-kB signaling pathway was found to be significantly elevated in SIRT5 KO cells by GO annotation and KEGG pathway functional enrichment analysis. We also confirmed that SIRT5 can bind PI3K by immunoprecipitation analysis.

CONCLUSION: This study is the first to demonstrate a relationship between SIRT5 and PCa metastasis, suggesting that SIRT5-mediated inhibition of the PI3K/AKT/NF-kB pathway is reduced in CRPC cells.