Amino acid starvation induced autophagic cell death in PC-12 cells: Evidence for activation of caspase-3 but not calpain-1 |
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Authors: | Shankar Sadasivan Anu Waghray Stephen F. Larner William A. Dunn Jr. Ronald L. Hayes Kevin K. W. Wang |
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Affiliation: | (1) Center for Traumatic Brain Injury Studies, Department of Neuroscience, McKnight Brain Institute of the University of Florida, Gainesville, Florida;(2) Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry, McKnight Brain Institute of the University of Florida, 100 S. Newell Drive, Box 100256, Gainesville, FL 32610, USA;(3) Department of Biochemistry and Molecular Biology, University of Maryland, Rockville, Maryland;(4) Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida |
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Abstract: | While the apoptotic and necrotic cell death pathways have been well studied, there lacks a comprehensive understanding of the molecular events involving autophagic cell death. We examined the potential roles of the apoptosis-linked caspase-3 and the necrosis/apoptosis-linked calpain-1 after autophagy induction under prolonged amino acid (AA) starvation conditions in PC-12 cells. Autophagy induction was observed as early as three hours following amino acid withdrawal. Cell death, measured by lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays occurred within 24 h following starvation and was accompanied by an upregulation in caspase-3 activity but not calpain-1. The cell death that occurred following AA starvation was significantly alleviated by treatment with the autophagy inhibitor 3-methyl adenine but not with the broad spectrum caspase inhibitors. Thus, this study demonstrates that 3-methyladenine-sensitive autophagic cell death due to AA starvation in PC-12 cells is mechanistically and biochemically similar to, yet distinct from, classic caspase dependent apoptosis. Shankar Sadasivan and Anu Waghray have contributed equally to this work. |
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Keywords: | Autophagy Autophagic cell death Apoptosis Necrosis Calpain-1 Caspases Spectrin breakdown product |
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