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Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs

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Item Type:Article
Title:Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs
Creators Name:Planells-Cases, R. and Lutter, D. and Guyader, C. and Gerhards, N.M. and Ullrich, F. and Elger, D.A. and Kucukosmanoglu, A. and Xu, G. and Voss, F.K. and Reincke, S.M. and Stauber, T. and Blomen, V.A. and Vis, D.J. and Wessels, L.F. and Brummelkamp, T.R. and Borst, P. and Rottenberg, S. and Jentsch, T.J.
Abstract:Although platinum‐based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume‐regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8‐dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug‐induced apoptosis independently from drug uptake, possibly by impairing VRAC‐dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D‐containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.
Keywords:Chloride Channel, Haploid Cell Screen, Swelling-Activated, VSOAC, VSOR
Source:EMBO Journal
Publisher:EMBO Press / Wiley
Page Range:2993-3008
Date:December 2015
Official Publication:https://doi.org/10.15252/embj.201592409
PubMed:View item in PubMed

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