Combined effect of protein kinase B inhibitor or extracellular signal-regulated kinase inhibitor against farnesyltransferase inhibition-induced apoptosis in SiHa cells.
The present study investigated the combined effect of Akt or extracellular signal-regulated kinase (ERK) inhibition in the presence of farnesyltransferase inhibitor against human cervix and uterus tumor cell line SiHa cells. Farnesyltransferase inhibitor may induce apoptosis through the mitochondria-mediated process and inhibition of the MEK, ERK, and Akt activity. Inhibitors of Akt and ERK at low concentrations seem to prevent the farnesyltransferase inhibitor-induced apoptosis in cervical SiHa cells by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and caspase-3 activation. These effects may be associated with inhibition of the reactive oxygen species formation and glutathione depletion. In contrast, at higher concentrations more than 1 microM, the Akt inhibitor and ERK inhibitor seem to exhibit an additive toxic effect against farnesyltransferase inhibitor-induced apoptosis by increasing mitochondrial membrane permeability change and oxidative stress, which may not involve inhibition of MEK, ERK, and Akt activity.
Department of Obstetrics and Gynecology, KonKuk University Hospital, KonKuk University, Seoul, 143-729, South Korea. leecs@cau.ac.kr
Sun Joo
SJ
Lee
Chung Soo
CS
Lee
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D051231:Farnesyltranstransferase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D005978:Glutathione