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

I. Ling Hsu, Cheng-Yang Chou, Yi Ying Wu, Jia En Wu, Chen Hsien Liang, Yao Tsung Tsai, Jhen Yu Ke, Yuh-Ling Chen, Keng-Fu Hsu, Tse-Ming Hong

Research output: Contribution to journalArticle

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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, upregulation 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.

Original languageEnglish
Pages (from-to)62925-62938
Number of pages14
JournalOncotarget
Volume7
Issue number39
DOIs
Publication statusPublished - 2016 Jan 1

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Cardiac Glycosides
Carcinoma
Growth
Neoplasms
Biomarkers
Digitoxin
Digoxin
Autophagy
Platinum

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Hsu, I. Ling ; Chou, Cheng-Yang ; Wu, Yi Ying ; Wu, Jia En ; Liang, Chen Hsien ; Tsai, Yao Tsung ; Ke, Jhen Yu ; Chen, Yuh-Ling ; Hsu, Keng-Fu ; Hong, Tse-Ming. / Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 39. pp. 62925-62938.
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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, upregulation 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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Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma. / Hsu, I. Ling; Chou, Cheng-Yang; Wu, Yi Ying; Wu, Jia En; Liang, Chen Hsien; Tsai, Yao Tsung; Ke, Jhen Yu; Chen, Yuh-Ling; Hsu, Keng-Fu; Hong, Tse-Ming.

In: Oncotarget, Vol. 7, No. 39, 01.01.2016, p. 62925-62938.

Research output: Contribution to journalArticle

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AU - Hong, Tse-Ming

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