title: Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate.
abstract: Cisplatin resistance is a major challenge in the treatment of cancer and develops through reduced drug accumulation and an increased ability to avoid drug-induced cell damage, cell shrinkage, and hence initiation of apoptosis. Uptake and release of the semiessential amino acid taurine contribute to cell volume homeostasis, and taurine has been reported to have antiapoptotic effects. Here we find that volume-sensitive taurine release in cisplatin-sensitive [wild-type (WT)] human ovarian cancer A2780 cells is reduced in the presence of the phospholipase A2 inhibitor bromenol lactone, the 5-lipoxygenase (5-LO) inhibitor ETH 615-139, and the cysteine leukotriene receptor 1 (CysLT1) antagonist zafirlukast and impaired by the anion channel blocker DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonate). Comparing WT and cisplatin-resistant (RES) A2780 cells we also find that evasion of cisplatin-induced cell death in RES A2780 cells correlates with an increased accumulation of taurine, due to an increased taurine uptake and a concomitant impairment of the volume-sensitive taurine release pathway, as well an inability to reduce cell volume after osmotic cell swelling. Downregulation of volume-sensitive taurine release in RES A2780 cells correlates with reduced expression of the leucine-rich repeat-containing protein 8A (LRRC8A). Furthermore, acute (18 h) exposure to cisplatin (5-10 μM) increases taurine release and LRRC8A expression in WT A2780 cells whereas cisplatin has no effect on LRRC8A expression in RES A2780 cells. It is suggested that shift in LRRC8A activity can be used as biomarker for apoptotic progress and acquirement of drug resistance.
authors.affiliation: Department of Biology, Section of Cellular and Developmental Biology, The August Krogh Building, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Belinda Halling
authors.initials: BH
authors.lastname: Sørensen
authors.affiliation: Department of Biology, Section of Cellular and Developmental Biology, The August Krogh Building, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Unnur Arna
authors.initials: UA
authors.lastname: Thorsteinsdottir
authors.affiliation: Department of Biology, Section of Cellular and Developmental Biology, The August Krogh Building, University of Copenhagen, Copenhagen, Denmark ihlambert@bio.ku.dk.
authors.forename: Ian Henry
authors.initials: IH
authors.lastname: Lambert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006706:Homeostasis; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009997:Osmotic Pressure; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology; D013654:Taurine / Q000378:metabolism*; D013997:Time Factors; D000099247:Taurine Transporters
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002945:Cisplatin; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D064801:Phospholipase A2 Inhibitors; D013654:Taurine; D000099247:Taurine Transporters; C485976:LRRC8A protein, human
keywords: LRRC8A; TauT; cell volume regulation; drug resistance; key word: platinum drugs