Calyculin A from Discodermia Calyx Is a Dual ActionToxin that Blocks Calcium Influx and Inhibits Protein Ser/Thr Phosphatases |
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Authors: | Maja Holy David L Brautigan |
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Institution: | 1. Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Email: ;2. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22910, USA |
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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. |
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Keywords: | phosphatases PP1 PP2A cyclin D1 calcium channels cell cycle MDA-MB-231 MDA-MB-468 MCF-7 ARPE-19 |
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