Ultraviolet light-induced apoptotic death is impaired by the HMG-CoA reductase inhibitor lovastatin.

Abstract

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.

• Authors: Renate v Bardeleben, Bernd Kaina, Gerhard Fritz
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 307 Issue 2 Pg. 401-7 (Jul 25 2003) ISSN: 0006-291X [Print] United States
• PMID: 12859971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lovastatin
• Mitogen-Activated Protein Kinase 8
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspases
• rac GTP-Binding Proteins

Topics

• Animals
• Apoptosis (radiation effects)
• CHO Cells
• Caspases (metabolism)
• Cricetinae
• DNA Replication
• Enzyme Activation
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Lovastatin (pharmacology)
• Mitogen-Activated Protein Kinase 8
• Mitogen-Activated Protein Kinases (metabolism)
• Ultraviolet Rays
• p38 Mitogen-Activated Protein Kinases
• rac GTP-Binding Proteins (metabolism)