The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G0/G1 and Induces p21WAF1/CIP1/SDI1 in a p53-independent Manner*
- From the §H. Lee Moffitt Cancer Center and Research Institute, Department of Biochemistry and Molecular Biology at the University of South Florida, Tampa, Florida 33612 and‡School of Medicine, Department of Pharmacology and the¶School of Arts and Science, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Abstract
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.
Footnotes
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↵* This work was supported by National Institutes of Health Grant U19-CA-67771.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence may be addressed: Dept. of Chemistry, Yale University, New Haven, CT 06511. Tel.: 203-432-5570; Fax: 203-432-3221; E-mail: ahamilton{at}ursula.chem.yale.edu.
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↵** To whom correspondence and reprint requests should be addressed: H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-979-6734; Fax: 813-979-6748; E-mail:sebti{at}moffitt.usf.edu.
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↵1 The abbreviations used are: FTase, farnesyltransferase; GGTase-I, geranylgeranyltransferase-I; IL, interleukin; CDK, cyclin-dependent kinase; TGF-β, transforming growth factor-β; PAGE, polyacrylamide gel electrophoresis.
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↵2 J. Sun, Y. Qian, A. D. Hamilton and S. M. Sebti, unpublished results.
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↵3 E. Lerner, Y. Qian, A. D. Hamilton and S. M. Sebti, unpublished results.
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↵4 W. Stark, P. Davies, A. D. Hamilton and S. M. Sebti, unpublished results.
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- Received May 14, 1997.
- Revision received August 11, 1997.
