Premium
Subunit composition of VRAC channels determines substrate specificity and cellular resistance to P t‐based anti‐cancer drugs
Author(s) -
PlanellsCases Rosa,
Lutter Darius,
Guyader Charlotte,
Gerhards Nora M,
Ullrich Florian,
Elger Deborah A,
Kucukosmanoglu Asli,
Xu Guotai,
Voss Felizia K,
Reincke S Momsen,
Stauber Tobias,
Blomen Vincent A,
Vis Daniel J,
Wessels Lodewyk F,
Brummelkamp Thijn R,
Borst Piet,
Rottenberg Sven,
Jentsch Thomas J
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201592409
Subject(s) - biology , protein subunit , cancer , composition (language) , microbiology and biotechnology , substrate specificity , substrate (aquarium) , genetics , biochemistry , gene , enzyme , ecology , linguistics , philosophy
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.