Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma
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I-Ling Hsu1, Cheng-Yang Chou2, Yi-Ying Wu3, Jia-En Wu1, Chen-Hsien Liang1, Yao-Tsung Tsai1, Jhen-Yu Ke4, Yuh-Ling Chen1,4, Keng-Fu Hsu2,3 and Tse-Ming Hong1,3
1Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4Institute of Oral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Tse-Ming Hong, email: [email protected]
Yuh-Ling Chen, email: [email protected]
Keng-Fu Hsu, email: [email protected]
Keywords: FXYD2, ovarian clear cell carcinoma, Na+/K+-ATPase, cardiac glycoside
Received: June 29, 2015 Accepted: January 17, 2016 Published: February 19, 2016
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.
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