This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Du, W.
Right arrow Articles by Prendergast, G. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Du, W.
Right arrow Articles by Prendergast, G. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 1999, p. 1831-1840, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cell Growth Inhibition by Farnesyltransferase Inhibitors Is Mediated by Gain of Geranylgeranylated RhoB

Wei Du, Peter F. Lebowitz, and George C. Prendergast*

The Wistar Institute, Philadelphia, Pennsylvania 19104

Received 16 July 1998/Returned for modification 8 September 1998/Accepted 19 November 1998

Recent results have shown that the ability of farnesyltransferase inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously that farnesylated Rho proteins are important targets for alternation by FTIs, based on studies of RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with loss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in Ras-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects were similar to FTI treatment insofar as they were all induced in transformed cells but not in normal cells. RhoB-GG did not promote anoikis of Ras-transformed cells, implying that this response to FTIs involves loss-of-function effects. Our findings corroborate the FTI-Rho hypothesis and demonstrate that gain-of-function effects on Rho are part of the drug mechanism. Gain of RhoB-GG may explain how FTIs inhibit the growth of human tumor cells that lack Ras mutations.

* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104. Phone: (215) 898-3792. Fax: (215) 898-2205. E-mail: prendergast{at}wista.wistar.upenn.edu.

Molecular and Cellular Biology, March 1999, p. 1831-1840, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Li, Z., Wang, C., Jiao, X., Katiyar, S., Casimiro, M. C., Prendergast, G. C., Powell, M. J., Pestell, R. G. (2008). Alternate Cyclin D1 mRNA Splicing Modulates p27KIP1 Binding and Cell Migration. J. Biol. Chem. 283: 7007-7015 [Abstract] [Full Text]  
  • Haas-Kogan, D. A., Banerjee, A., Kocak, M., Prados, M. D., Geyer, J. R., Fouladi, M., McKnight, T., Poussaint, T. Y., Broniscer, A., Blaney, S. M., Boyett, J. M., Kun, L. E. (2008). Phase I trial of tipifarnib in children with newly diagnosed intrinsic diffuse brainstem glioma. Neuro Oncol 10: 341-347 [Abstract] [Full Text]  
  • Arana-Yi, C., Quintas-Cardama, A., Giles, F., Thomas, D., Carrasco-Yalan, A., Cortes, J., Kantarjian, H., Verstovsek, S. (2006). Advances in the Therapy of Chronic Idiopathic Myelofibrosis. The Oncologist 11: 929-943 [Abstract] [Full Text]  
  • Wang, C.-C., Liao, Y.-P., Mischel, P. S., Iwamoto, K. S., Cacalano, N. A., McBride, W. H. (2006). HDJ-2 as a Target for Radiosensitization of Glioblastoma Multiforme Cells by the Farnesyltransferase Inhibitor R115777 and the Role of the p53/p21 Pathway.. Cancer Res. 66: 6756-6762 [Abstract] [Full Text]  
  • Oh, S.-H., Kim, W.-Y., Kim, J.-H., Younes, M. N., El-Naggar, A. K., Myers, J. N., Kies, M., Cohen, P., Khuri, F., Hong, W. K., Lee, H.-Y. (2006). Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 12: 653-661 [Abstract] [Full Text]  
  • Basso, A. D., Kirschmeier, P., Bishop, W. R. (2006). Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors. J. Lipid Res. 47: 15-31 [Abstract] [Full Text]  
  • Berzat, A. C., Buss, J. E., Chenette, E. J., Weinbaum, C. A., Shutes, A., Der, C. J., Minden, A., Cox, A. D. (2005). Transforming Activity of the Rho Family GTPase, Wrch-1, a Wnt-regulated Cdc42 Homolog, Is Dependent on a Novel Carboxyl-terminal Palmitoylation Motif. J. Biol. Chem. 280: 33055-33065 [Abstract] [Full Text]  
  • Zhong, W-B, Liang, Y-C, Wang, C-Y, Chang, T-C, Lee, W-S (2005). Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting Rho geranylgeranylation and RhoA/ROCK signaling. Endocr Relat Cancer 12: 615-629 [Abstract] [Full Text]  
  • Appels, N. M.G.M., Beijnen, J. H., Schellens, J. H.M. (2005). Development of Farnesyl Transferase Inhibitors: A Review. The Oncologist 10: 565-578 [Abstract] [Full Text]  
  • Fernandez-Borja, M., Janssen, L., Verwoerd, D., Hordijk, P., Neefjes, J. (2005). RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1. J. Cell Sci. 118: 2661-2670 [Abstract] [Full Text]  
  • Gomez-Benito, M., Marzo, I., Anel, A., Naval, J. (2005). Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination. Mol. Pharmacol. 67: 1991-1998 [Abstract] [Full Text]  
  • Ferguson, D., Rodriguez, L. E., Palma, J. P., Refici, M., Jarvis, K., O'Connor, J., Sullivan, G. M., Frost, D., Marsh, K., Bauch, J., Zhang, H., Lin, N.-H., Rosenberg, S., Sham, H. L., Joseph, I. B.J.K. (2005). Antitumor Activity of Orally Bioavailable Farnesyltransferase Inhibitor, ABT-100, Is Mediated by Antiproliferative, Proapoptotic, and Antiangiogenic Effects in Xenograft Models. Clin. Cancer Res. 11: 3045-3054 [Abstract] [Full Text]  
  • Tabernero, J., Rojo, F., Marimon, I., Voi, M., Albanell, J., Guix, M., Vazquez, F., Carulla, J., Cooper, M., Andreu, J., Van Vreckem, A., Bellmunt, J., Manne, V., Manning, J. A., Garrido, C., Felip, E., del Campo, J. M., Garcia, M., Valverde, S., Baselga, J. (2005). Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors. JCO 23: 2521-2533 [Abstract] [Full Text]  
  • Zimmerman, T. M., Harlin, H., Odenike, O. M., Berk, S., Sprague, E., Karrison, T., Stock, W., Larson, R. A., Ratain, M. J., Gajewski, T. F. (2004). Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies. JCO 22: 4816-4822 [Abstract] [Full Text]  
  • Kamasani, U., Huang, M., DuHadaway, J. B., Prochownik, E. V., Donover, P. S., Prendergast, G. C. (2004). Cyclin B1 Is a Critical Target of RhoB in the Cell Suicide Program Triggered by Farnesyl Transferase Inhibition. Cancer Res. 64: 8389-8396 [Abstract] [Full Text]  
  • Wherlock, M., Gampel, A., Futter, C., Mellor, H. (2004). Farnesyltransferase inhibitors disrupt EGF receptor traffic through modulation of the RhoB GTPase. J. Cell Sci. 117: 3221-3231 [Abstract] [Full Text]  
  • Jiang, K., Sun, J., Cheng, J., Djeu, J. Y., Wei, S., Sebti, S. (2004). Akt Mediates Ras Downregulation of RhoB, a Suppressor of Transformation, Invasion, and Metastasis. Mol. Cell. Biol. 24: 5565-5576 [Abstract] [Full Text]  
  • Ellis, M. (2004). Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition. The Oncologist 9: 20-26 [Abstract] [Full Text]  
  • Running, M. P., Lavy, M., Sternberg, H., Galichet, A., Gruissem, W., Hake, S., Ori, N., Yalovsky, S. (2004). Enlarged meristems and delayed growth in plp mutants result from lack of CaaX prenyltransferases. Proc. Natl. Acad. Sci. USA 101: 7815-7820 [Abstract] [Full Text]  
  • Ryan, D. P., Eder, J. P. Jr., Puchlaski, T., Seiden, M. V., Lynch, T. J., Fuchs, C. S., Amrein, P. C., Sonnichsen, D., Supko, J. G., Clark, J. W. (2004). Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors. Clin. Cancer Res. 10: 2222-2230 [Abstract] [Full Text]  
  • Lancet, J. E., Karp, J. E. (2003). Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy. Blood 102: 3880-3889 [Abstract] [Full Text]  
  • Brunner, T. B., Hahn, S. M., Gupta, A. K., Muschel, R. J., McKenna, W. G., Bernhard, E. J. (2003). Farnesyltransferase Inhibitors: An Overview of the Results of Preclinical and Clinical Investigations. Cancer Res. 63: 5656-5668 [Abstract] [Full Text]  
  • Selleri, C., Maciejewski, J. P., Montuori, N., Ricci, P., Visconte, V., Serio, B., Luciano, L., Rotoli, B. (2003). Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells. Blood 102: 1490-1498 [Abstract] [Full Text]  
  • Johnston, S. R.D., Hickish, T., Ellis, P., Houston, S., Kelland, L., Dowsett, M., Salter, J., Michiels, B., Perez-Ruixo, J. J., Palmer, P., Howes, A. (2003). Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer. JCO 21: 2492-2499 [Abstract] [Full Text]  
  • McKenna, S., Eatock, M. (2003). The Medical Management of Pancreatic Cancer: A Review. The Oncologist 8: 149-160 [Abstract] [Full Text]  
  • Druker, B. J. (2003). Overcoming Resistance to Imatinib by Combining Targeted Agents. Molecular Cancer Therapeutics 2: 225-226 [Full Text]  
  • Cortes, J., Albitar, M., Thomas, D., Giles, F., Kurzrock, R., Thibault, A., Rackoff, W., Koller, C., O'Brien, S., Garcia-Manero, G., Talpaz, M., Kantarjian, H. (2003). Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 101: 1692-1697 [Abstract] [Full Text]  
  • Solski, P. A., Helms, W., Keely, P. J., Su, L., Der, C. J. (2002). RhoA Biological Activity Is Dependent on Prenylation but Independent of Specific Isoprenoid Modification. Cell Growth Differ. 13: 363-373 [Abstract] [Full Text]  
  • Lobell, R. B., Liu, D., Buser, C. A., Davide, J. P., DePuy, E., Hamilton, K., Koblan, K. S., Lee, Y., Mosser, S., Motzel, S. L., Abbruzzese, J. L., Fuchs, C. S., Rowinsky, E. K., Rubin, E. H., Sharma, S., Deutsch, P. J., Mazina, K. E., Morrison, B. W., Wildonger, L., Yao, S.-L., Kohl, N. E. (2002). Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Type-I. Molecular Cancer Therapeutics 1: 747-758 [Abstract] [Full Text]  
  • Adnane, J., Muro-Cacho, C., Mathews, L., Sebti, S. M., Munoz-Antonia, T. (2002). Suppression of Rho B Expression in Invasive Carcinoma from Head and Neck Cancer Patients. Clin. Cancer Res. 8: 2225-2232 [Abstract] [Full Text]  
  • van Golen, K. L., Bao, L., DiVito, M. M., Wu, Z., Prendergast, G. C., Merajver, S. D. (2002). Reversion of RhoC GTPase-induced Inflammatory Breast Cancer Phenotype by Treatment with a Farnesyl Transferase Inhibitor. Molecular Cancer Therapeutics 1: 575-583 [Abstract] [Full Text]  
  • Bergo, M. O., Ambroziak, P., Gregory, C., George, A., Otto, J. C., Kim, E., Nagase, H., Casey, P. J., Balmain, A., Young, S. G. (2002). Absence of the CAAX Endoprotease Rce1: Effects on Cell Growth and Transformation. Mol. Cell. Biol. 22: 171-181 [Abstract] [Full Text]  
  • Zhang, B., Prendergast, G. C., Fenton, R. G. (2002). Farnesyltransferase Inhibitors Reverse Ras-mediated Inhibition of Fas Gene Expression. Cancer Res. 62: 450-458 [Abstract] [Full Text]  
  • Arceci, R. J., Longley, B. J., Emanuel, P. D. (2002). Atypical Cellular Disorders. ASH Education Book 2002: 297-314 [Abstract] [Full Text]  
  • Liu, A.-X., Rane, N., Liu, J.-P., Prendergast, G. C. (2001). RhoB Is Dispensable for Mouse Development, but It Modifies Susceptibility to Tumor Formation as Well as Cell Adhesion and Growth Factor Signaling in Transformed Cells. Mol. Cell. Biol. 21: 6906-6912 [Abstract] [Full Text]  
  • Rose, W. C., Lee, F. Y. F., Fairchild, C. R., Lynch, M., Monticello, T., Kramer, R. A., Manne, V. (2001). Preclinical Antitumor Activity of BMS-214662, a Highly Apoptotic and Novel Farnesyltransferase Inhibitor. Cancer Res. 61: 7507-7517 [Abstract] [Full Text]  
  • Caldelari, D., Sternberg, H., Rodriguez-Concepcion, M., Gruissem, W., Yalovsky, S. (2001). Efficient Prenylation by a Plant Geranylgeranyltransferase-I Requires a Functional CaaL Box Motif and a Proximal Polybasic Domain. Plant Physiol. 126: 1416-1429 [Abstract] [Full Text]  
  • Feldkamp, M. M., Lau, N., Roncari, L., Guha, A. (2001). Isotype-specific Ras{middle dot}GTP-Levels Predict the Efficacy of Farnesyl Transferase Inhibitors against Human Astrocytomas Regardless of Ras Mutational Status. Cancer Res. 61: 4425-4431 [Abstract] [Full Text]  
  • Karp, J. E., Lancet, J. E., Kaufmann, S. H., End, D. W., Wright, J. J., Bol, K., Horak, I., Tidwell, M. L., Liesveld, J., Kottke, T. J., Ange, D., Buddharaju, L., Gojo, I., Highsmith, W. E., Belly, R. T., Hohl, R. J., Rybak, M. E., Thibault, A., Rosenblatt, J. (2001). Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97: 3361-3369 [Abstract] [Full Text]  
  • Adjei, A. A., Davis, J. N., Bruzek, L. M., Erlichman, C., Kaufmann, S. H. (2001). Synergy of the Protein Farnesyltransferase Inhibitor SCH66336 and Cisplatin in Human Cancer Cell Lines. Clin. Cancer Res. 7: 1438-1445 [Abstract] [Full Text]  
  • Reichert, A., Heisterkamp, N., Daley, G. Q., Groffen, J. (2001). Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood 97: 1399-1403 [Abstract] [Full Text]  
  • Peters, D. G., Hoover, R. R., Gerlach, M. J., Koh, E. Y., Zhang, H., Choe, K., Kirschmeier, P., Bishop, W. R., Daley, G. Q. (2001). Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 97: 1404-1412 [Abstract] [Full Text]  
  • End, D. W., Smets, G., Todd, A. V., Applegate, T. L., Fuery, C. J., Angibaud, P., Venet, M., Sanz, G., Poignet, H., Skrzat, S., Devine, A., Wouters, W., Bowden, C. (2001). Characterization of the Antitumor Effects of the Selective Farnesyl Protein Transferase Inhibitor R115777 in Vivo and in Vitro. Cancer Res. 61: 131-137 [Abstract] [Full Text]  
  • Reuveni, H., Geiger, T., Geiger, B., Levitzki, A. (2000). Reversal of the Ras-induced Transformed Phenotype by HR12, a Novel Ras Farnesylation Inhibitor, Is Mediated by the Mek/Erk Pathway. JCB 151: 1179-1192 [Abstract] [Full Text]  
  • Baron, R., Fourcade, E., Lajoie-Mazenc, I., Allal, C., Couderc, B., Barbaras, R., Favre, G., Faye, J.-C., Pradines, A. (2000). RhoB prenylation is driven by the three carboxyl-terminal amino acids of the protein: Evidenced in vivo by an anti-farnesyl cysteine antibody. Proc. Natl. Acad. Sci. USA 97: 11626-11631 [Abstract] [Full Text]  
  • Reuter, C. W. M., Morgan, M. A., Bergmann, L. (2000). Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?. Blood 96: 1655-1669 [Abstract] [Full Text]  
  • Liu, A.-x., Du, W., Liu, J.-P., Jessell, T. M., Prendergast, G. C. (2000). RhoB Alteration Is Necessary for Apoptotic and Antineoplastic Responses to Farnesyltransferase Inhibitors. Mol. Cell. Biol. 20: 6105-6113 [Abstract] [Full Text]  
  • Favoni, R. E., De Cupis, A. (2000). The Role of Polypeptide Growth Factors in Human Carcinomas: New Targets for a Novel Pharmacological Approach. Pharmacol. Rev. 52: 179-206 [Abstract] [Full Text]  
  • Adjei, A. A., Davis, J. N., Erlichman, C., Svingen, P. A., Kaufmann, S. H. (2000). Comparison of Potential Markers of Farnesyltransferase Inhibition. Clin. Cancer Res. 6: 2318-2325 [Abstract] [Full Text]  
  • Law, B. K., Norgaard, P., Moses, H. L. (2000). Farnesyltransferase Inhibitor Induces Rapid Growth Arrest and Blocks p70s6k Activation by Multiple Stimuli. J. Biol. Chem. 275: 10796-10801 [Abstract] [Full Text]  
  • Zujewski, J., Horak, I. D., Bol, C. J., Woestenborghs, R., Bowden, C., End, D. W., Piotrovsky, V. K., Chiao, J., Belly, R. T., Todd, A., Kopp, W. C., Kohler, D. R., Chow, C., Noone, M., Hakim, F. T., Larkin, G., Gress, R. E., Nussenblatt, R. B., Kremer, A. B., Cowan, K. H. (2000). Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer. JCO 18: 927-927 [Abstract] [Full Text]  
  • Emanuel, P. D., Snyder, R. C., Wiley, T., Gopurala, B., Castleberry, R. P. (2000). Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors. Blood 95: 639-645 [Abstract] [Full Text]  
  • Jiang, K., Coppola, D., Crespo, N. C., Nicosia, S. V., Hamilton, A. D., Sebti, S. M., Cheng, J. Q. (2000). The Phosphoinositide 3-OH Kinase/AKT2 Pathway as a Critical Target for Farnesyltransferase Inhibitor-Induced Apoptosis. Mol. Cell. Biol. 20: 139-148 [Abstract] [Full Text]  
  • Du, W., Prendergast, G. C. (1999). Geranylgeranylated RhoB Mediates Suppression of Human Tumor Cell Growth by Farnesyltransferase Inhibitors. Cancer Res. 59: 5492-5496 [Abstract] [Full Text]  
  • Russell, J. S., Lang, F. F., Huet, T., Janicot, M., Chada, S., Wilson, D. R., Tofilon, P. J. (1999). Radiosensitization of Human Tumor Cell Lines Induced by the Adenovirus-mediated Expression of an Anti-Ras Single-Chain Antibody Fragment. Cancer Res. 59: 5239-5244 [Abstract] [Full Text]  
  • Du, W., Liu, A., Prendergast, G. C. (1999). Activation of the PI3'K-AKT Pathway Masks the Proapoptotic Effects of Farnesyltransferase Inhibitors. Cancer Res. 59: 4208-4212 [Abstract] [Full Text]  
  • Si, X., Zeng, Q., Ng, C. H., Hong, W., Pallen, C. J. (2001). Interaction of Farnesylated PRL-2, a Protein-tyrosine Phosphatase, with the beta -Subunit of Geranylgeranyltransferase II. J. Biol. Chem. 276: 32875-32882 [Abstract] [Full Text]  
  • Liu, A.-x., Cerniglia, G. J., Bernhard, E. J., Prendergast, G. C. (2001). RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage. Proc. Natl. Acad. Sci. USA 98: 6192-6197 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»