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

Rosa Planells-Cases, Darius Lutter, Charlotte Guyader, Nora M. Gerhards, Florian Ullrich, Deborah A. Elger, Asli Kucukosmanoglu, Guotai Xu, Felizia K. Voss, S. Momsen Reincke, Tobias Stauber, Vincent A. Blomen, Daniel J. Vis, Lodewyk F. Wessels, Thijn R. Brummelkamp, Piet Borst, Sven Rottenberg*, Thomas J. Jentsch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2993-3008
Number of pages16
JournalEMBO Journal
Volume34
Issue number24
DOIs
Publication statusPublished - 14 Dec 2015

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