Cadmium-induced autophagy and apoptosis are mediated by a calcium signaling pathway |
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Authors: | S H Wang Y L Shih W C Ko Y H Wei C M Shih |
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Institution: | (1) Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC;(2) Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan, ROC;(3) School of Medical Laboratory Science and Biotechnology, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC;(4) Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC;(5) Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, 112, Taiwan, ROC;(6) Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC |
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Abstract: | The cytotoxicity of cadmium (Cd) induced autophagy and apoptosis in MES-13 cells was determined by flow cytometry. Autophagy
was also assessed by formation of autophagosomes and processing of LC3. Pharmacological inhibition of autophagy resulted in
increased of cell viability, suggesting autophagy plays a role in cell death in Cd-treated mesangial cells. Cd also induced
a rapid elevation in cytosolic calcium (Ca2+]i ), and modulation of Ca2+]i via treatment with IP
3R inhibitor or knockdown of calcineurin resulted in a change in the proportion of cell death, suggesting that the release
of calcium from the ER plays a crucial role in Cd-induced cell death. Inhibition of Cd-induced ERK activation by PD 98059
suppressed Cd-induced autophagy, and BAPTA-AM eliminated activation of ERK. BAPTA-AM also inhibited Cd-induced mitochondrial
depolarization and activation of caspases. These findings demonstrated that Cd induces both autophagy and apoptosis through
elevation of Ca2+]i, followed by Ca2+-ERK and Ca2+-mitochondria-caspase signaling pathways.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 05 July 2008; received after revision 25 August 2008; accepted 17 September 2008 |
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Keywords: | " target="_blank"> Autophagy apoptosis cadmium calcium calcineurin ERK mitochondria |
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