title: Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma.
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.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: I-Ling
authors.initials: IL
authors.lastname: Hsu
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
authors.affiliation: Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jia-En
authors.initials: JE
authors.lastname: Wu
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chen-Hsien
authors.initials: CH
authors.lastname: Liang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yao-Tsung
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Institute of Oral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jhen-Yu
authors.initials: JY
authors.lastname: Ke
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Oral Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yuh-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Keng-Fu
authors.initials: KF
authors.lastname: Hsu
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism; D002301:Cardiac Glycosides / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D002301:Cardiac Glycosides; C416502:FXYD2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: FXYD2; Na+/K+-ATPase; cardiac glycoside; ovarian clear cell carcinoma