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.

Cytogenotoxic effects of Adenium obesum seeds extracts on breast cancer cells

“…As anticancer agents, cardiac glycosides triggered different cell death mechanisms including the intrinsic or the extrinsic pathway of apoptosis (Schneider et al, 2018, Juncker et al, 2011). Furthermore, cardiac glycosides induced autophagic cell death was described in breast, ovarian, colorectal, and lung cancer cells (Farah et al, 2016, Hsu et al, 2016, Kang et al, 2016, Wang et al, 2012). More recently, the ability of cardiac glycosides to trigger immunogenic cell death were reported (Diederich et al, 2017).…”

Identifying osteosarcoma metastasis associated genes by weighted gene co-expression network analysis (WGCNA)

“…Deficiency of FXYD2 led to tumor growth suppression, which indicated that FXYD2 had the possibility to be antitumor target. [ 32 ]…”

Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death

“…As anticancer agents, CGs triggered different cell death mechanisms including the intrinsic or the extrinsic apoptosis (Juncker et al, 2011 ; Cerella et al, 2015 ). Furthermore, CG-induced autophagic cell death was described in breast (Farah et al, 2016 ), ovarian (Hsu et al, 2016 ), colorectal (Kang et al, 2016 ), nerve system (Radogna et al, 2016 ), or lung cancer cells (Wang et al, 2012 ). More recently, the ability of CGs to trigger anoikis (Pongrakhananon et al, 2014 ) and immunogenic cell death (Menger et al, 2012 , 2013 ; Diederich et al, 2017 ) were reported.…”