Abstract 351: 2-Methoxyestradiol targets RON kinase and FLIP to inhibit epithelial-mesenchymal transition in prostate cancer

Abstract

Abstract Prostate Cancer (PCA) is the second leading cause of cancer-related deaths among men in the United States. Despite significant progress in our understanding of prostate biology, early detection and treatment, the five-year survival for hormone refractory metastatic prostate cancer (HRPCA) patients is less than 30%. Current therapies targeting PCA are not effective against the metastatic stage. 2-Methoxyestradiol (2-ME2) is a metabolic product of 17-β-estradiol and is found in trace amounts in the body; it has shown anti-tumorigenic properties in multiple cancer models. Previous studies from our lab have shown that 2-ME2 can induce apoptosis in PCA cells by blocking cell cycle progression, and also inhibits PCA growth and progression in TRAMP mice. However, the precise mechanism of action of 2-ME2 has not yet been elucidated. In order to classify the mechanism behind PCA inhibition by 2-ME2, we tested its effectiveness on an array containing genes associated with epithelial-mesenchymal transition (EMT). We identified Recepteur d'Origine Nantais (RON) as one of the most significantly downregulated genes in response to 2-ME2 treatment. RON has been shown to promote cell invasiveness, migration, survivability, and proliferation in many cancers such as breast, colon, lung, and pancreatic. However, very little is known about RON's signaling mechanism in PCA. We've found RON to be highly increased in advanced stage PCA cell lines. RON knockdown shows a concomitant decrease in the expression of FLICE-like inhibitory protein (FLIP). FLIP is an anti-apoptotic protein which prevents death receptor-induced apoptotic signaling. FLIP has been found to promote EMT as well as androgen-independent PCA growth. Stimulation with the RON ligand HGF yielded elevated expression of RON and FLIP in PCA cell lines while treatment with 2-ME2 caused downregulation. Immunoprecipitation experiments showed RON to be associated with the androgen-induced proliferation inhibitor (APRIN) in PCA cells. Our data suggest that RON/FLIP crosstalk plays a role in prostate cancer. Therefore, targeting RON/FLIP signaling could have potential therapeutic benefit for metastatic PCA. Supported by NIH CA 135451 (APK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 351. doi:1538-7445.AM2012-351