Targeting ribosomal S-6 kinase for the prevention and treatment of liver injury and liver fibrosis.
Activation of hepatic stellate cells (HSC) is responsible for the development of liver fibrosis in chronic liver diseases of all causes, and remarkably, HSC clearance by apoptosis may allow recovery from liver injury and reversal of liver fibrosis. Because in preclinical studies it has been shown that activation of ribosomal S-6 kinase (RSK) and phosphorylation of the CCAAT/enhancer-binding protein (C/EBP) beta in activated HSC is critical for the progression of liver fibrosis, RSK has been considered as a therapeutic target for the liver fibrosis. Unexpectedly, preclinical studies documented a strong antiinflammatory effect of RSK inhibitors, decreasing liver injury induced by hepatotoxins. Therefore, RSK inhibitors reduce liver fibrosis directly by inducing apoptosis of activated HSC, and indirectly by preventing liver injury and inflammation. The activation of RSK and C/EBPbeta phosphorylation also occurs in human liver fibrosis. Thus, appropriate RSK inhibitors may be beneficial in the prevention and treatment of liver injury and liver fibrosis. These issues will be discussed in this review.
Moores Cancer Center, University of California, San Diego, California, USA. mbuck@ucsd.edu
Martina
M
Buck
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D047428:Protein Kinase Inhibitors; D053218:Receptors, Death Domain; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D053181:Caspase 8