Abstract 4381: Phosphatase of regenerating liver-3 (PRL-3): a novel metastatic taret for prostate cancer.

Abstract

Abstract Prostate carcinoma (PCa) is one of the most frequently diagnosed cancers in US men causing an estimated 30,000 deaths annually. The primary cause for deaths related to PCa is the development of metastases. Although these patients initially respond to traditional androgen ablation therapy, they invariably develop metastasis and shortened life span following treatment failure. What causes metastases in PCa patients remains poorly understood. Recently, Phosphatase of Regenerating Liver-3 (PRL-3) has been discovered as a unique gene involved in the promotion of metastasis of several cancers including colorectal cancer, ovarian cancer, breast cancer, cervical cancer, and lung cancer. However, its involvement in PCa metastases is not yet known. Our current studies utilizing chromosomal microarray analysis confirmed that PRL-3 gene is amplified in prostate cancer. Additional studies conducted using real-time PCR and Western blot analyses confirmed that PRL-3 is overexpressed in advanced prostate cancer cells. To determine the functional significance of PRL-3 expression in PCa pathology, we designed a series of studies (cell proliferation, anchorage-independent growth, and migration assays as endpoints) to therapeutically target PRL-3 expression using DU145 and PC-3 metastatic cell lines as model systems. Targeting PRL-3 expression either by RNAi or by pharmacological inhibition using 5-[[5-bromo-2-[(2-bromophenyl)methoxy]phenyl]methylene]-2-thioxo-4-thiazolidinone resulted in substantial reduction of PCa cell proliferation, anchorage-independent growth and migration ability of these PCa cells. Furthermore, we identified dibenzoyl methane (DBM), a curcumin analog present in licorice root, as a potential non-toxic natural inhibitor of PRL-3 in PCa cells. Specifically, DBM treatment downregulated the expression of PRL-3 resulting in the inhibition of cell proliferation, loss of anchorage-independent growth and mitigating the motility of PC-3 and DU145 cells in vitro. Importantly, administration of DBM to nude mice bearing prostate tumors derived from PC-3 and DU145 cells resulted in regression of these tumors. To gain further mechanistic insights into how PRL-3 expression promotes aggressive traits in PCa cells, cell signaling studies were carried out using panel of PCa cell lines. These studies revealed that Translationally Controlled Tumor Protein and dsRNA dependent protein kinase R may be important mediators of PRL-3 aggressive behavior in PCa cells. Our results for the first time show that PRL-3 may have a prominent role in the progression of PCa and may serve as a potential prognostic and therapeutic target for advanced PCa. Citation Format: Jyotsna Sundar, Joseph Devito, Michael Tyrkus, Maarten C. Bosland, André Kajdacsy-Balla, Gnanasekar Munirathinam. Phosphatase of regenerating liver-3 (PRL-3): a novel metastatic taret for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4381. doi:10.1158/1538-7445.AM2013-4381