Damage to mitochondrial respiration chain is related to phospholipase A2 activation caused by tumor necrosis factor.
Tumor necrosis factor (TNF) has been shown to be cytotoxic to tumor cell lines in vitro, but the mechanism by which TNF exerts its cell growth-regulatory effects is not known. In this report, we used various inhibitors to investigate the sequence of events that lead to cytotoxic effects of TNF on L.P3 cells, a highly sensitive, murine fibroblast cell line. Our results indicate that mitochondrial respiration chains are damaged by a hydroxyl radical at an early stage of the cell lysis after TNF treatment. This event is followed by the activation of phospholipase A2, and finally leads to cell lysis.
Higuchi
M
M
Division of Chemical Toxicology and Immunochemistry, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Shirotani
K
K
Higashi
N
N
Toyoshima
S
S
Osawa
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D008555:Melitten / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects*; D010741:Phospholipases A / Q000187:drug effects*; D054467:Phospholipases A2; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005609:Free Radicals; D006878:Hydroxides; D014409:Tumor Necrosis Factor-alpha; D008555:Melitten; D016718:Arachidonic Acid; D017665:Hydroxyl Radical; D010741:Phospholipases A; D054467:Phospholipases A2