Abstract 6393: Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in males and there is no effective therapeutics to treat aggressive metastatic PCa (~70% mortality rate). We previously reported that the α1 Na/K-ATPase (α1 NKA), the product of ATP1A1 gene, is a tumor suppressor protein whose expression was significantly reduced in primary tumor and further reduced in the bone metastatic lesions (≤10% of normal tissue). Here we show that loss of cell surface expression of ATP1A1 induces Epithelial Mesenchymal Transition (EMT), and promotes metastatic potential and tumor growth of PCa by decreasing E-cadherin expression and upregulating c-Myc expression via Src-dependent signaling. The progressive loss of α1 NKA in PCa is because of increased endocytosis by activating the α1 NKA/Src receptor complex. Using a unique α1 NKA screening platform, we have discovered MB5, an inverse agonist of receptor α1 NKA that can block ouabain, an agonist-induced signaling and endocytosis of α1 NKA. Functionally, MB5 treatment increased the expression of α1 NKA and E cadherin-which reversed EMT and decreased the invasion and growth of tumor xenografts. Thus, we have revealed a hitherto unrecognized mechanism that regulates the EMT and invasiveness, and identified α1 NKA inverse agonists such as MB5 as a potential drug candidate for the treatment of aggressive PCa. Citation Format: Moumita Banerjee, Zhichuan Li, Yingnyu Gao, Minqi Huang, Liquan Cai, Tianyan Gao, Xie Zijian. Targeting the increased endocytosis of Na/K ATPase α1 subunit as a new therapeutic approach to prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6393.