Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells.
Acquired resistance to chemotherapeutic drugs in cancer cells can reflect an ability to limit cellular drug availability, to repair drug induced DNA damage, and to limit initiation/progression of cell death (apoptosis). The leucine-rich-repeat-containing 8A (LRRC8A) protein is an essential component of volume sensitive channels for organic osmolytes (VSOAC) and volume regulated anion channels (VRAC), which are activated during the apoptotic process. Here we illustrate that cisplatin resistance in human ovarian cancer cells (A2780) correlates with a reduced expression of LRRC8A and copper transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B). We also find that cisplatin (Pt) accumulation correlates with LRRC8A protein expression and channel activity, i.e., the cellular Pt content is high when VSOAC is activated by depolarization of the plasma membrane or hypoosmotic cell swelling, and reduced when channel activity/LRRC8A expression is reduced by genetically silencing/pharmacological inhibition, or the cells have acquired a resistant phenotype with low LRRC8A protein expression. It is suggested that reduced LRRC8A expression in cisplatin-resistant A2780 cells ensures cell survival through limitation in cisplatin accumulation and a concomitant reduction in osmolytes loss via VSOAC/VRAC and hence instigation of the apoptotic process.
University of Copenhagen, Department of Biology, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.
Belinda Halling
BH
Sørensen
University of Copenhagen, Department of Biology, Universitetsparken 13, 2100 Copenhagen Ø, Denmark; University of Copenhagen, Department of Pharmacy, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
Celina Støving
CS
Dam
University of Copenhagen, Department of Pharmacy, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
Stefan
S
Stürup
University of Copenhagen, Department of Biology, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.
Ian Henry
IH
Lambert
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C490079:SLC31A1 protein, human; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin
Apoptotic volume decrease; Cisplatin; Drug resistance; Leucine rich repeat containing 8 protein; Taurine