Abstract
Abstract Prostate cancer (PC) is one of the most common cancers in men. Unfortunately, limited treatment options currently exist for those who have developed advanced castration-resistant PC (CRPC). G-1 is a GPER1/GPR30 agonist, and a promising candidate for CRPC therapy. G-1 is effective in halting the growth of CR tumors but not those grown in intact hosts. These findings suggest GPER1 is a therapeutic target for CRPC. We found that G-1, through activation of GPER1, inhibited growth of CRPC cells via cell-cycle arrest at the G2-M phase, probably leading to mitotic catastrophy. However, the exact mode of action of G-1 was not known. To better understand the pathways involved in G-1 action, we conducted a genome-wide mRNA-seq and miRNA-seq study on G-1 treated xenografts. We identified a panel of novel G-1-associated tumor suppressive miRNAs and genes. Moreover, Ingenuity Pathway Analysis revealed that the G-1 differentially regulated genes are involved in “Cellular Growth and Proliferation”, “endocrine function” and “Cancer” pathways. We validated the expression of the key miRNA (miR-34c, miR-10b, miR-138 and miR218) and genes in G-1 treated castration resistant xenografts and cell lines (C4-2 and 22Rv1). Furthermore, we have shown the tumor suppressor function of these miRNA in cell survival, migration, and invasion. The predicted target genes were next examined for decreased expression by qRT-PCR. We confirmed decreased expression of some of the downstream targets, which consist of genes involved in cell cycle regulation (CCNA and CCND, CDK1, CDK4, PLK1), cell survival (Bcl2, Survivin), cell migration/F-actin formation (LASP, PCDH7, ITGA9, ROBO1, SLIT1) and G2/M checkpoint (CDK1, PLK1, BCL-2 Survivin). Thus these miRNAs - miR-34c, miR-10b, miR-138 and miR218 - are ideal candidates for therapy of CRPC. Citation Format: Pheruza Tarapore, Sarah To, Bin Ouyang, Yuet-Kin Leung, Ana Cheong, Shuk-mei Ho. MicroRNA targeting anti-apoptotic and G2/M pathways as therapeutic targets for castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2537. doi:10.1158/1538-7445.AM2017-2537
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