Ultraviolet light-induced apoptotic death is impaired by the HMG-CoA reductase inhibitor lovastatin.
HMG-CoA reductase inhibitors (i.e., statins) attenuate C-terminal isoprenylation of Rho GTPases, thereby inhibiting UV-C-induced activation of c-Jun-N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs). Inhibition of UV-C-triggered JNK/SAPK activation by lovastatin is due to inhibition of Rac-SEK1/MKK4-mediated phosphorylation of JNKs/SAPKs at Thr183/Tyr185. UV-C-stimulated phosphorylation of p38 kinase (Thr180/Tyr182) is also impaired by lovastatin. Cell killing provoked by UV-C irradiation was significantly inhibited by lovastatin. This was paralleled by a reduced frequency of chromosomal aberrations, accelerated recovery from UV-C-induced transient replication blockage, inhibition of Chk1 kinase activation and impaired cyclinB1 expression. Furthermore, UV-C-induced activation of caspases and apoptotic death was largely reduced by lovastatin. Inhibition of JNK/SAPK by transient overexpression of dominant-negative JNK1/SAPK1 also conferred resistance to UV-C light and attenuated activation of caspase 3. Based on the data, we suggest that lovastatin-provoked resistance to UV-C light is due to the inhibition of UV-C-inducible Rac-SEK1/MKK4-JNK/SAPK-dependent signal mechanisms regulating cell cycle progression and activation of caspases and apoptotic death.
Bardeleben
Renate v
Rv
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Germany.
Kaina
Bernd
B
Fritz
Gerhard
G
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D016466:CHO Cells; D020169:Caspases / Q000378:metabolism; D006224:Cricetinae; D004261:DNA Replication; D004789:Enzyme Activation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D020744:rac GTP-Binding Proteins