ArticleThe EMBO journal2015
Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs.
Article in The EMBO journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers.
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Who cites it
178 citing papers in PubMed, 254 citations in OpenAlex.
- The intracellular subdomain of the volume-regulated anion channel subunit LRRC8A is a hotspot of channel activation.Nature communications · 2026Article
- Structures of the volume-regulated anion channel LRRC8A/D in activating and inhibiting conditions.Nature communications · 2026Article
- LRRC8A as a candidate biomarker of cisplatin sensitivity in muscle-invasive bladder cancer: an exploratory immunohistochemical study.International urology and nephrology · 2026Article
- Insights from three decades of BRCA1/2 modeling in mice.Nature genetics · 2026Review
- Subunit-specific roles of LRRC8 proteins in determining glutamate permeability of astrocytic volume-regulated anion channels.American journal of physiology. Cell physiology · 2026Article
- LRRC8A Inhibition Overcomes Chemoresistance by Downregulating MRP3 and CYP3A4 in the 3D Spheroid Model of Human Breast Cancer Cells.International journal of molecular sciences · 2026Article
- LRRC8A: A multifaceted regulator in cancer, neurological disorders, metabolic diseases and immune modulation.Genes & diseases · 2026Review
- VRAC coordinates the trade-off between nutrient absorption and antimicrobial defense in enterocytes against inflammation.Nature communications · 2026Article
- Mechanism of action of two potent LRRC8/VRAC channel inhibitors.Research square · 2026Article
- USP18 Impacts Cisplatin Resistance in Ovarian Cancer Cells by Modulating DNA Repair.International journal of biological sciences · 2026Article
- CD109 Drives Stemness and Chemoresistance in Colorectal Cancer via LRRC8A/AKAP12/PKCα-Mediated STAT3 Activation and WNT Signaling.International journal of biological sciences · 2026Article
- Exploring the selective inhibitory effects of Flavoxate and its analogues on two chloride channels and neuronal action potentials.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2026Article
- GATOR1 complex controls cisplatin sensitivity.Cell death & disease · 2025Article
- Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.Molecular cell · 2025Article
- Assembly and lipid-gating of LRRC8A:D volume-regulated anion channels.Nature communications · 2025Article
- Colorectal Cancer at the Crossroads: The Good, the Bad, and the Future of Platinum-Based Drugs.Chemical reviews · 2025Review
- LRRC8A Regulates Outer Hair Cell Volume and Electromotility and is Required for Hearing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake.Communications biology · 2025Article
- Excitotoxic neuronal death requires superoxide entry into neurons through volume-regulated anion channels.Science advances · 2025Article
- Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels.bioRxiv : the preprint server for biology · 2025Article
118 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.