GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells.
The mechanism by which the geranylgeranyltransferase I inhibitor GGTI-298 and the farnesyltransferase inhibitor FTI-277 inhibit human tumor growth is not known. Herein, we demonstrate that in the human lung adenocarcinoma A549 cells, GGTI-298 induced a G1-G0 block whereas FTI-277 induced an enrichment in the G2-M phase of the cell cycle. Although FTI-277, GGTI-298, and compactin inhibited A549 cell growth, only GGTI-298 and compactin induced apoptosis as demonstrated by four criteria: 4',6-diamidine-2-phenylindoledihydrochloride staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, DNA fragmentation assay, and flow cytometry. Furthermore, the involvement of geranylgeranylated proteins in apoptotic pathways was confirmed by demonstrating that geranylgeraniol was able to block the ability of compactin to induce apoptosis. These results suggest that protein geranylgeranylation is critical for the control of programmed cell death and that, in A549 cells, farnesylated and geranylgeranylated proteins are involved in G2-M and G0-G1, respectively.
Miquel
K
K
Laboratoire d'Oncologie Cellulaire et Moléculaire, EA 2048, Faculté des Sciences Pharmaceutiques and Centre de Lutte contre le Cancer Claudius Regaud, Toulouse, France.
Pradines
A
A
Sun
J
J
Qian
Y
Y
Hamilton
A D
AD
Sebti
S M
SM
Favre
G
G
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D019883:Alkyl and Aryl Transferases; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D014166:Transferases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D001549:Benzamides; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D008715:Methionine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I