Ha-rasVal12 oncogene increases susceptibility of NIH/3T3 cells to lovastatin.
This study demonstrates that Ha-rasVal12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-ras transformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-ras activity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-ras activity but induced WAF1 activity and disrupted the cell population in G0/G1 and S phases. The Ha-ras transformants expressing either dominant negative RasAsn17 or Raf-1CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-ras activity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.
Chang
M Y
MY
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Jan
M S
MS
Won
S J
SJ
Liu
H S
HS
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation; D015870:Gene Expression; D019254:Genes, bcl-2; D011905:Genes, ras; D007399:Interphase; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016196:S Phase; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016328:NF-kappa B; D007544:Isopropyl Thiogalactoside; D008148:Lovastatin; D019908:Proto-Oncogene Proteins c-raf; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D018631:ras Proteins