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Volume 272, Number 43, Issue of October 24, 1997 pp. 27224-27229
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G₀/G₁ and Induces p21^{WAF1/CIP1/SDI1} in a p53-independent Manner

(Received for publication, May 14, 1997, and in revised form, August 11, 1997)

Andreas Vogt , Jiazhi Sun ^§ , Yimin Qian ^¶ , Andrew D. Hamilton ^¶ and Saïd M. Sebti ^§

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

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 p21^WAF. HT-1080 and A-549 cells had a high basal level of p21^WAF, and GGTI-298 did not further increase these levels. Furthermore, GGTI-298 also induces the accumulation of large amounts of p21^WAF 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 p27^KIP as well as cyclin E and cyclin D1. These results demonstrate that GGTase-I inhibitors arrest cells in G₀/G₁ and induce accumulation of p21^WAF in a p53-independent manner and that FTase inhibitors can interfere with cell cycle events by a mechanism that involves neither p21^WAF nor p27^KIP. The results also point to the potential of GGTase-I inhibitors as agents capable of restoring growth arrest in cells lacking functional p53.

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