Crosstalk between Na+,K+-ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells

Takuto Fujii, Takahiro Shimizu, Shota Yamamoto, Keisuke Funayama, Kyosuke Fujita, Yoshiaki Tabuchi, Akira Ikari, Hiroshi Takeshima, Hideki Sakai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Low concentrations of cardiac glycosides including ouabain, digoxin, and digitoxin block cancer cell growth without affecting Na+,K+-ATPase activity, but the mechanism underlying this anti-cancer effect is not fully understood. Volume-regulated anion channel (VRAC) plays an important role in cell death signaling pathway in addition to its fundamental role in the cell volume maintenance. Here, we report cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na+,K+-ATPase and VRAC in human cancer cells. Submicromolar concentrations of ouabain enhanced VRAC currents concomitantly with a deceleration of cancer cell proliferation. The effects of ouabain were abrogated by a specific inhibitor of VRAC (DCPIB) and knockdown of an essential component of VRAC (LRRC8A), and they were also attenuated by the disruption of membrane microdomains or the inhibition of NADPH oxidase. Digoxin and digitoxin also showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges, and these effects were blocked by DCPIB. In membrane microdomains of cancer cells, LRRC8A was found to be co-immunoprecipitated with Na+,K+-ATPase α1-isoform. These ouabain-induced effects were not observed in non-cancer cells. Therefore, cardiac glycosides were considered to interact with Na+,K+-ATPase to stimulate the production of reactive oxygen species, and they also apparently activated VRAC within membrane microdomains, thus producing anti-proliferative effects.

Original languageEnglish
Pages (from-to)3792-3804
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number11
DOIs
StatePublished - 2018/11

Keywords

  • Cancer cells
  • Membrane microdomains
  • Na,K-ATPase
  • Ouabain
  • Volume-regulated anion channel

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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