Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma

Abstract

// I-Ling Hsu 1 , Cheng-Yang Chou 2 , Yi-Ying Wu 3 , Jia-En Wu 1 , Chen-Hsien Liang 1 , Yao-Tsung Tsai 1 , Jhen-Yu Ke 4 , Yuh-Ling Chen 1, 4 , Keng-Fu Hsu 2, 3 and Tse-Ming Hong 1, 3 1 Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3 Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 4 Institute of Oral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan Correspondence to: Tse-Ming Hong, email: tmhong@mail.ncku.edu.tw Yuh-Ling Chen, email: yuhling@mail.ncku.edu.tw Keng-Fu Hsu, email: d5580@mail.ncku.edu.tw Keywords: FXYD2, ovarian clear cell carcinoma, Na + /K + -ATPase, cardiac glycoside Received: June 29, 2015     Accepted: January 17, 2016     Published: February 19, 2016 ABSTRACT Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na + /K + -ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients’ prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na + /K + -ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, up-regulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na + /K + -ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo . Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC.