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Molecular and Cellular Biology, November 2007, p. 8003-8014, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00057-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth{triangledown}

Samuel C. Falsetti,1,2 De-an Wang,1,2 Hairuo Peng,4 Dora Carrico,4 Adrienne D. Cox,3 Channing J. Der,3 Andrew D. Hamilton,4 and Saïd M. Sebti1,2*

Drug Discovery Program, The H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida,1 Departments of Interdisciplinary Oncology and Molecular Medicine, The University of South Florida, Tampa, Florida,2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,3 Yale University, Department of Chemistry, New Haven, Connecticut4

Received 11 January 2007/ Returned for modification 5 March 2007/ Accepted 4 September 2007

Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorage-independent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27Kip1 protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.

* Corresponding author. Mailing address: 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 745-6734. Fax: (813) 745-6748. E-mail: said.sebti{at}moffitt.org

{triangledown} Published ahead of print on 17 September 2007.

Molecular and Cellular Biology, November 2007, p. 8003-8014, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.00057-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lu, J., Chan, L., Fiji, H. D.G., Dahl, R., Kwon, O., Tamanoi, F. (2009). In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Molecular Cancer Therapeutics 8: 1218-1226 [Abstract] [Full Text]  
  • Kazi, A., Carie, A., Blaskovich, M. A., Bucher, C., Thai, V., Moulder, S., Peng, H., Carrico, D., Pusateri, E., Pledger, W. J., Berndt, N., Hamilton, A., Sebti, S. M. (2009). Blockade of Protein Geranylgeranylation Inhibits Cdk2-Dependent p27Kip1 Phosphorylation on Thr187 and Accumulates p27Kip1 in the Nucleus: Implications for Breast Cancer Therapy. Mol. Cell. Biol. 29: 2254-2263 [Abstract] [Full Text]  
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