title: (-)-Englerin A-evoked Cytotoxicity Is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase.
abstract: (-)-Englerin A ((-)-EA) has a rapid and potent cytotoxic effect on several types of cancer cell that is mediated by plasma membrane ion channels containing transient receptor potential canonical 4 (TRPC4) protein. Because these channels are Ca2+-permeable, it was initially thought that the cytotoxicity arose as a consequence of Ca2+overload. Here we show that this is not the case and that the effect of (-)-EA is mediated by a heteromer of TRPC4 and TRPC1 proteins. Both TRPC4 and TRPC1 were required for (-)-EA cytotoxicity; however, although TRPC4 was necessary for the (-)-EA-evoked Ca2+elevation, TRPC1 was not. TRPC1 either had no role or was a negative regulator of Ca2+entry. By contrast, both TRPC4 and TRPC1 were necessary for monovalent cation entry evoked by (-)-EA, and (-)-EA-evoked cell death was dependent upon entry of the monovalent cation Na+We therefore hypothesized that Na+/K+-ATPase might act protectively by counteracting the Na+load resulting from sustained Na+entry. Indeed, inhibition of Na+/K+-ATPase by ouabain potently and strongly increased (-)-EA-evoked cytotoxicity. The data suggest that (-)-EA achieves cancer cell cytotoxicity by inducing sustained Na+entry through heteromeric TRPC1/TRPC4 channels and that the cytotoxic effect of (-)-EA can be potentiated by Na+/K+-ATPase inhibition.
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Ludlow
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gaunt
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Hussein N
authors.initials: HN
authors.lastname: Rubaiy
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Musialowski
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Blythe
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and.
authors.forename: Naveen S
authors.initials: NS
authors.lastname: Vasudev
authors.affiliation: the School of Pharmacy, Aichi-Gakuin University, 1-100 Kusumoto, Chikusa, Nagoya 464-8650, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.affiliation: From the Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom and D.J.Beech@leeds.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Beech
mesh_terms: D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D003603:Cytotoxins; D009363:Neoplasm Proteins; D045789:Sesquiterpenes, Guaiane; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C534971:englerin A; C096351:transient receptor potential cation channel, subfamily C, member 1; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+/K+-ATPase; calcium; cancer; cell death; ouabain; sodium; transient receptor potential channels (TRP channels)