Arachidonic acid enhances caffeine-induced cell death via caspase-independent cell death.
Caffeine is a globally consumed psychostimulant but can be fatal to cells at overdose exposures. Although caspase-dependent apoptosis plays a role in caffeine-induced cell death, the responsible intracellular signalling cascade remains incompletely understood. The cellular slime mould, Dictyostelium discoideum, does not possess caspase-dependent apoptotic machinery. Here, we observed that ablation of D. discoideumplaA, which encodes a phospholipase A2 (PLA₂) homolog, leads to a decreased rate of cell death under high caffeine concentrations and to enhanced cell death with the addition of arachidonic acid. Moreover, the inhibition of PLA₂ activity lead to a recovery of the survival rate in caspase-inhibited Hela cervical carcinoma cells under high caffeine concentrations, indicating that caffeine-induced cell death is enhanced via PLA₂-dependent signalling. Our results indicate that arachidonic acid may be a general second messenger that negatively regulates caffeine tolerance via a caspase-independent cell death cascade, which leads to multiple effects in eukaryotic cells.
Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Tennodai 1-1-1, Ibaraki 305-8572, Japan. hidekuwayama@biol.tsukuba.ac.jp
Hidekazu
H
Kuwayama
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016718:Arachidonic Acid / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004023:Dictyostelium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D054467:Phospholipases A2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016718:Arachidonic Acid; D002110:Caffeine; D000242:Cyclic AMP; D054467:Phospholipases A2; D020169:Caspases