title: Amino acid starvation induced autophagic cell death in PC-12 cells: evidence for activation of caspase-3 but not calpain-1.
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.
authors.affiliation: Department of Neuroscience, Center for Traumatic Brain Injury Studies, McKnight Brain Institute of the University of Florida, Gainesville, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Sadasivan
authors.forename: Anu
authors.initials: A
authors.lastname: Waghray
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Larner
authors.forename: William A
authors.initials: WA
authors.lastname: Dunn
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hayes
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002403:Cathepsins / Q000378:metabolism; D002467:Cell Nucleus / Q000648:ultrastructure; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051381:Rats; D013049:Spectrin / Q000378:metabolism; D013217:Starvation / Q000378:metabolism*; D013995:Time; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D061945:Caspase Inhibitors; D013049:Spectrin; D007770:L-Lactate Dehydrogenase; D002403:Cathepsins; D002154:Calpain; D053148:Caspase 3