title: Protolichesterinic Acid, Isolated from the Lichen Cetraria islandica, Reduces LRRC8A Expression and Volume-Sensitive Release of Organic Osmolytes in Human Lung Epithelial Cancer Cells.
abstract: We have tested the effect of protolichesterinic acid (PA) on the activity of the volume-sensitive release pathway for the organic osmolyte taurine (VSOAC) and the expression of the leucine-rich-repeat-channel 8A (LRRC8A) protein, which constitutes an essential VSOAC component. Exposing human lung cancer cells (A549) to PA (20 µg/mL, 24 h) reduces LRRC8A protein expression by 25% and taurine release following osmotic cell swelling (320 → 200 mOsm) by 60%. C75 (20 µg/mL, 24 h), a γ-lactone with a C8 carbon fatty acid chain, reduces VSOAC activity by 30%, i.e. less than PA. Stearic acid (20 µg/mL, 24 h) has no effect on VSOAC. Hence, length of PA's fatty acid chain adds to γ-lactone's inhibitory action. 5-Lipoxygenase (5-LO) activity is essential for swelling-induced activation of VSOAC. PA has no effect on cellular concentration of leukotrienes (5-HETE/LTB4 ) under hypotonic conditions, excluding that PA mediated inhibition of VSOAC involves 5-LO inhibition. A549 cells exposed to the chemotherapeutic drug cisplatin (10 μM, 24 h) reveal signs of apoptosis, i.e. 25% reduction in cell viability as well as 1.3-, 1.5- and 3.3-fold increase in the expression of LRRC8A, Bax (regulator of apoptosis) and p21 (regulator of cell cycle progression), respectively. PA reduces cell viability by 30% but has no effect on p21/Bax expression. This excludes PA as a pro-apoptotic drug in A549 cells.
authors.affiliation: Department of Biology, Section of Cell biology and Physiology, University of Copenhagen, 13 Universitetsparken, Copenhagen, DK-2100, Denmark.|School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, 101, Reykjavik, Iceland.
authors.forename: Unnur Arna
authors.initials: UA
authors.lastname: Thorsteinsdottir
authors.affiliation: School of Health Sciences, Faculty of Pharmaceutical Sciences, University of Iceland, 101, Reykjavik, Iceland.
authors.forename: Margret
authors.initials: M
authors.lastname: Thorsteinsdottir
authors.affiliation: Department of Biology, Section of Cell biology and Physiology, University of Copenhagen, 13 Universitetsparken, Copenhagen, DK-2100, Denmark.
authors.forename: Ian Henry
authors.initials: IH
authors.lastname: Lambert
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008011:Lichens / Q000737:chemistry*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D000068837:Parmeliaceae / Q000737:chemistry*; D013654:Taurine / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006893:Hydroxyeicosatetraenoic Acids; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D051028:bcl-2-Associated X Protein; C095781:protolichesterinic acid; D013654:Taurine; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; D015107:4-Butyrolactone; D002945:Cisplatin
keywords: Bax; C75; arachidonic acid mobilization; cisplatin; p21; taurine