Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells.
Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer drugs that show promise in blocking the growth of tumors. Here, we report that FTIs are capable of inducing apoptosis of transformed but not untransformed cells. Treatment of v-K-ras-transformed normal rat kidney (KNRK) cells with FTIs leads to the induction of apoptotic cell morphology, chromatin condensation and DNA fragmentation. In addition, fluorescence-activated cell sorter analysis of FTI-treated KNRK cells shows a sub-G1 apoptotic peak (chromosome content of <2 N). This FTI-induced apoptosis is evident only when the cells are grown in low serum conditions (0.1% fetal calf serum) and is observed selectively with transformed KNRK cells and not with untransformed NRK cells. Further analysis of the mechanism underlying this apoptosis has shown that FTI treatment of KNRK cells results in the activation of caspase 3 but not caspase 1. Moreover, the addition of Z-DEVD-fmk, an agent that interferes with caspase 3 activity, can inhibit FTI-induced apoptosis in a dose-dependent manner. Introduction of the CASP-3 gene into MCF7 cells, which lack caspase 3 activity, results in a significant increase of FTI-induced apoptosis. Furthermore, FTI induces the release of cytochrome c into the cytosol. This release is an important feature of caspase 3-mediated apoptosis. These results suggest that FTIs induce apoptosis through the release of cytochrome c from the mitochondria resulting in caspase 3 activation.
Suzuki
N
N
Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, 1602 Molecular Sciences Building, 405 Hilgard Avenue, Los Angeles, CA 90095-1489, USA.
Urano
J
J
Tamanoi
F
F
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002461:Cell Line, Transformed; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D007211:Indoles; D007668:Kidney; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C007293:DAPI; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin