文献类型： 外文期刊

作者： Banerjee, Moumita ¹ ; Li, Zhichuan ² ; Gao, Yingnyu ¹ ; Lai, Fangfang ² ; Huang, Minqi ¹ ; Zhang, Zhongbing ² ; Cai, L ¹ ;

作者机构： 1.Marshall Univ, Marshall Inst Interdisciplinary Res MIIR, Huntington, WV 25755 USA

2.Univ Toledo Hlth Sci Campus, Dept Physiol Pharmacol & Med, Toledo, OH USA

3.Shanghai Acad Agr Sci, Inst Edible Fungi, Shanghai, Peoples R China

4.Peking Union Med Coll, Inst Materia Med, Beijing, Peoples R China

5.Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, Beijing, Peoples R China

6.Marshall Univ, Joan Edwards Sch Med, Dept Surg, Huntington, WV USA

7.Univ Kentucky, Markey Canc Res Ctr, Dept Mol & Cellular Biochem, Lexington, KY USA

关键词： EMT; inverse agonist; metastasis; Na/K-ATPase; prostate cancer

期刊名称：PROSTATE （ 影响因子：3.279； 五年影响因子：3.288 ）

ISSN： 0270-4137

年卷期：

页码：

收录情况： SCI

摘要： The surface expression of Na/K-ATPase alpha 1 (NKA) is significantly reduced in primary prostate tumors and further decreased in bone metastatic lesions. Here, we show that the loss of cell surface expression of NKA induces epithelial-mesenchymal transition (EMT) and promotes metastatic potential and tumor growth of prostate cancer (PCa) by decreasing the expression of E-cadherin and increasing c-Myc expression via the activation of Src/FAK pathways. Mechanistically, reduced surface expression of NKA in PCa is due to increased endocytosis through the activation of NKA/Src receptor complex. Using a high-throughput NKA ligand-screening platform, we have discovered MB5 as an inverse agonist of the NKA/Src receptor complex, capable of blocking the endocytosis of NKA. MB5 treatment increased NKA expression and E-cadherin in PCa cells, which reversed EMT and consequently decreased the invasion and growth of spheroid models and tumor xenografts. Thus, we have identified a hitherto unrecognized mechanism that regulates EMT and invasiveness of PCa and demonstrated for the first time the feasibility of identifying inverse agonists of receptor NKA/Src complex and their potential utility as anticancer drugs. We, therefore, conclude that cell surface expression of alpha 1 NKA can be targeted for the development of new therapeutics against aggressive PCa and that MB5 may serve as a prototype for drug development against EMT in metastatic PCa.