title: Calyculin A from Discodermia calyx is a dual action toxin that blocks calcium influx and inhibits protein Ser/Thr phosphatases.
abstract: Calyculin A (Caly A) is cell permeable toxin widely used in cell biology research as an inhibitor of type 1 and type 2A protein Ser/Thr phosphatases of the PPP family. Here we tested effects of low concentrations of Caly A on proliferation of human cancer and non-cancer cell lines. We found that long-term 0.3 nM Caly A prevented G1 to S phase cell cycle progression in human Hs-68 fibroblasts and ARPE19 epithelial cells, but not human breast cancer MDA-MB-468, MDA-MB-231 and MCF7 cells. These conditions produced no change in cyclin D1 levels or in the phosphorylation of endogenous proteins. However, acute application of 0.3 nM Caly A blocked serum-induced increase in intracellular calcium levels in Hs-68 fibroblasts, but not in MDA-MB-468 breast cancer cells. We propose that subnanomolar Caly A prevents cell cycle progression because it blocks calcium uptake by fibroblasts. This probably involves non-selective cation channels and cancer cell proliferation was not affected because calcium enters these cells by other channels. Our results suggest that calyculin A has dual actions and acts as a channel blocker, in addition to its well-established effects as a phosphatase inhibitor.
authors.affiliation: Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. mh5yu@virginia.edu
authors.forename: Maja
authors.initials: M
authors.lastname: Holy
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000633:toxicity; D002455:Cell Division; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D061986:MCF-7 Cells; D008387:Marine Toxins; D010080:Oxazoles / Q000633:toxicity*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation
chemical_list: D002121:Calcium Channel Blockers; D008387:Marine Toxins; D010080:Oxazoles; D019938:Cyclin D1; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D002118:Calcium