The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SD11) in a p53-independent manner

Andreas Vogt, Jiazhi Sun, Yimin Qian, Andrew D. Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

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, Pane-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 mounts 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.

Original languageEnglish (US)
Pages (from-to)27224-27229
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number43
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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