The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner.
Recently we have shown that in fibroblasts (NIH 3T3 and Rat-1 cells) inhibition of protein geranylgeranylation leads to a G0/G1 arrest, whereas inhibition of protein farnesylation does not affect cell cycle distribution. Here we demonstrate that in human tumor cells the geranylgeranyltransferase-I (GGTase-I) inhibitor GGTI-298 blocked cells in G0/G1, whereas the farnesyltransferase (FTase) inhibitor FTI-277 showed a differential effect depending on the cell line. FTI-277 accumulated Calu-1 and A-549 lung carcinoma and Colo 357 pancreatic carcinoma cells in G2/M, T-24 bladder carcinoma, and HT-1080 fibrosarcoma cells in G0/G1, but had no effect on cell cycle distribution of pancreatic (Panc-1), breast (SKBr 3 and MDAMB-231), and head and neck (A-253) carcinoma cells. Furthermore, treatment of Calu-1, Panc-1, Colo 357, T-24, A-253, SKBr 3, and MDAMB-231 cells with GGTI-298, but not FTI-277, induced the protein expression levels of the cyclin-dependent kinase inhibitor p21WAF. HT-1080 and A-549 cells had a high basal level of p21WAF, and GGTI-298 did not further increase these levels. Furthermore, GGTI-298 also induces the accumulation of large amounts of p21WAF mRNA in Calu-1 cells, a cell line that lacks the tumor suppressor gene p53. There was little effect of GGTI-298 on the cellular levels of another cyclin- dependent kinase inhibitor p27KIP as well as cyclin E and cyclin D1. These results demonstrate that GGTase-I inhibitors arrest cells in G0/G1 and induce accumulation of p21WAF in a p53-independent manner and that FTase inhibitors can interfere with cell cycle events by a mechanism that involves neither p21WAF nor p27KIP. The results also point to the potential of GGTase-I inhibitors as agents capable of restoring growth arrest in cells lacking functional p53.
Vogt
A
A
School of Medicine, Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Sun
J
J
Qian
Y
Y
Hamilton
A D
AD
Sebti
S M
SM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000494:pharmacology*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005354:Fibrosarcoma; D016193:G1 Phase; D006258:Head and Neck Neoplasms; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides; D010190:Pancreatic Neoplasms; D017368:Protein Prenylation; D016192:Resting Phase, Cell Cycle; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms
D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D009842:Oligopeptides; D016159:Tumor Suppressor Protein p53; D008148:Lovastatin; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I