Abstract 2708: The TWEAK-FN14 pathway promotes prostate cancer bone metastasis through the NFκB pathway.

Abstract

Abstract Advanced prostate cancer is highly associated with castration resistance and the development of bone metastases. Understanding the mechanisms contributing to prostate cancer bone metastasis is needed in order to develop novel therapeutic agents. NFκB signaling has been implicated in prostate cancer progression. The Tweak-Fn14 axis, which activates both canonical and non-canonical NFκB pathways, has been shown to be up-regulated in many cancer types. However, the role of the Tweak-Fn14 signaling in prostate cancer progression has not been investigated. In this study, we show that oncogenic Ras transformation of the AR negative, DU145 cell line led to the acquisition of bone metastatic capability and associated increased expression of TWEAK and FN14. Knocking down FN14 using shRNAs, as well as blocking the NFκB pathway using an IKBα super repressor, in DU145/Rasb1 cells, significantly inhibited bone metastasis and improved survival. This inhibitory effect of FN14shRNA was fully rescued by activating the NFκB canonical pathway, but not the NFκB non-canonical pathway. FN14 expression is also high in the bone metastatic, AR negative prostate cancer PC3 cell line. Similarly, knocking-down FN14 in PC3 cells inhibited bone metastatic capacity following intracardiac inoculation in a xenograft model. TWEAK and FN14 are relatively low or undetectable in AR positive prostate cancer cell lines including Lncap and 22RV1. AR binding was detected in both TWEAK and FN14 promoters as determined by chromatin immunoprecipitation analysis in Lncap. Reporter assays demonstrated that AR binding inhibited FN14 and TWEAK transcription. The above experimental models were further supported by analyses of publically available expression data sets for clinical prostate cancer samples that showed FN14 expression was inversely correlated with AR gene expression signatures. In addition, individual FN14 RNA mean expression was higher in clinical metastasis of castrate (n=11) as compared to non-castrate (n=8) patients. We propose that down-regulation of AR activity under castrate conditions may lead to increased FN14 expression and NFκB activation, which provides a survival benefit for prostate cancer cells associated with disease progression. Therefore, targeting the TWEAK-FN14 pathway in prostate cancer patients provides potential, new preventive and therapeutic approaches. Citation Format: Juan Juan Yin, Yen-Nien Liu, Ben Barrett, Lei Fang, Ross Lake, Orla Casey, Heather Tillman, Yvona Ward, Kathleen Kelly. The TWEAK-FN14 pathway promotes prostate cancer bone metastasis through the NFκB pathway. [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 2708. doi:10.1158/1538-7445.AM2013-2708