Ludlow, MJ, Gaunt, HJ, Rubaiy, HN orcid.org/0000-0002-1489-5576 et al. (5 more authors) (2017) (-)-Englerin A-evoked Cytotoxicity is Mediated by Na+ Influx and Counteracted by Na+/K+-ATPase. Journal of Biological Chemistry, 292 (2). pp. 723-731. ISSN 0021-9258
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 protein (TRPC4). Since 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Editors: |
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Copyright, Publisher and Additional Information: | © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY). |
Keywords: | transient receptor potential channels (TRP channels); calcium; sodium; Na+/K+-ATPase; ouabain; cell death; cancer |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Nov 2016 13:08 |
Last Modified: | 05 Oct 2017 16:21 |
Published Version: | https://doi.org/10.1074/jbc.M116.755678 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.M116.755678 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:108415 |