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[Cancer Research 57, 1846-1850, May 15, 1997]
© 1997 American Association for Cancer Research
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GGTI-298 Induces G0-G1 Block and Apoptosis Whereas FTI-277 Causes G2-M Enrichment in A549 Cells1

Karine Miquel, Anne Pradines, Jiazhi Sun, Yimin Qian, Andrew D. Hamilton, Saïd M. Sebti2 and Gilles Favre2

Laboratoire d'Oncologie Cellulaire et Moléculaire, EA 2048, Faculté des Sciences Pharmaceutiques and Centre de Lutte contre le Cancer Claudius Regaud, 20-24 rue du Pont Saint-Pierre, 31052 Toulouse Cedex, France [K. M., A. P., G. F.]; Department of Biochemistry and Molecular Biology and the H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612 [J. S., S. M. S.]; and School of Arts and Science, Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [Y. Q., A. D. H.]

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.

1 This work was supported by the Fédération Nationale des Centres de Recherche et de Lutte Contre le Cancer (G. F.), the Comités Départementaux de la Ligue Nationale de Lutte Contre le Cancer (Région Midi-Pyrénées: G. F.), and the Ministère de la Recherche et de l'Enseignement Supérieur (G. F.) and by NIH Grant CA-76661 (S. M. S., A. D. H.).

2 To whom requests for reprints should be addressed.

Received 1/29/97. Accepted 4/ 1/97.




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