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
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
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 Liu, A.-x.
Right arrow Articles by Prendergast, G. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liu, A.-x.
Right arrow Articles by Prendergast, G. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2000, p. 6105-6113, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

RhoB Alteration Is Necessary for Apoptotic and Antineoplastic Responses to Farnesyltransferase Inhibitors

Ai-xue Liu,1 Wei Du,1,2 Jeh-Ping Liu,3 Thomas M. Jessell,3 and George C. Prendergast1,2,*

The Wistar Institute, Philadelphia,1 and Glenolden Laboratory, DuPont Pharmaceuticals Company, Glenolden,2 Pennsylvania, and Department of Neurobiology, Columbia University, New York, New York3

Received 9 March 2000/Returned for modification 18 April 2000/Accepted 17 May 2000

Farnesyltransferase inhibitors (FTIs) are in clinical trials, but how they selectively inhibit malignant cell growth remains uncertain. One important player in this process appears to be RhoB, an endosomal Rho protein that regulates receptor trafficking. FTI treatment elicits a gain of the geranylgeranylated RhoB isoform (RhoB-GG) that occurs due to modification of RhoB by geranylgeranyltransferase I in drug-treated cells. Notably, this event is sufficient to mediate antineoplastic effects in murine models and human carcinoma cells. To further assess this gain-of-function mechanism and determine whether RhoB-GG has a necessary role in drug action, we examined the FTI response of murine fibroblasts that cannot express RhoB-GG due to homozygous deletion of the rhoB gene. Nullizygous (-/-) cells were susceptible to cotransformation by adenovirus E1A plus activated H-Ras but defective in their FTI response, despite complete inhibition of H-Ras prenylation. Actin cytoskeletal and phenotypic events were disrupted in -/- cells, implicating RhoB-GG in these effects. Interestingly, -/- cells were resistant to FTI-induced growth inhibition under anchorage-dependent but not anchorage-independent conditions, indicating that, while RhoB-GG is sufficient, it is not necessary for growth inhibition under all conditions. In contrast, -/- cells were resistant to FTI-induced apoptosis in vitro and in vivo. Significantly, the apoptotic defect of -/- cells compromised the antitumor efficacy of FTI in xenograft assays. This study offers genetic proof of the hypothesis that RhoB-GG is a crucial mediator of the antineoplastic effects of FTIs.

* Corresponding author. Mailing address: Glenolden Laboratory, DuPont Pharmaceuticals Company, Glenolden, PA 19036. Phone: (610) 237-7847. Fax: (610) 237-7937. E-mail: george.c.prendergast{at}dupontpharma.com.

Molecular and Cellular Biology, August 2000, p. 6105-6113, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Dai, Y., Chen, S., Pei, X.-Y., Almenara, J. A., Kramer, L. B., Venditti, C. A., Dent, P., Grant, S. (2008). Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells. Blood 112: 2439-2449 [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 Oncology 10: 341-347 [Abstract] [Full Text]  
  • Lajoie-Mazenc, I., Tovar, D., Penary, M., Lortal, B., Allart, S., Favard, C., Brihoum, M., Pradines, A., Favre, G. (2008). MAP1A Light Chain-2 Interacts with GTP-RhoB to Control Epidermal Growth Factor (EGF)-dependent EGF Receptor Signaling. J. Biol. Chem. 283: 4155-4164 [Abstract] [Full Text]  
  • Sandilands, E., Brunton, V. G., Frame, M. C. (2007). The membrane targeting and spatial activation of Src, Yes and Fyn is influenced by palmitoylation and distinct RhoB/RhoD endosome requirements. J. Cell Sci. 120: 2555-2564 [Abstract] [Full Text]  
  • Lancet, J. E., Gojo, I., Gotlib, J., Feldman, E. J., Greer, J., Liesveld, J. L., Bruzek, L. M., Morris, L., Park, Y., Adjei, A. A., Kaufmann, S. H., Garrett-Mayer, E., Greenberg, P. L., Wright, J. J., Karp, J. E. (2007). A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 109: 1387-1394 [Abstract] [Full Text]  
  • Ma, Y., Kuno, T., Kita, A., Asayama, Y., Sugiura, R. (2006). Rho2 Is a Target of the Farnesyltransferase Cpp1 and Acts Upstream of Pmk1 Mitogen-activated Protein Kinase Signaling in Fission Yeast. Mol. Biol. Cell 17: 5028-5037 [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]  
  • 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]  
  • Adjei, A. A., Hidalgo, M. (2005). Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy. JCO 23: 5386-5403 [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]  
  • Wang, D.-A., Sebti, S. M. (2005). Palmitoylated Cysteine 192 Is Required for RhoB Tumor-suppressive and Apoptotic Activities. J. Biol. Chem. 280: 19243-19249 [Abstract] [Full Text]  
  • Pan, J., She, M., Xu, Z.-X., Sun, L., Yeung, S.-C. J. (2005). Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells. Cancer Res. 65: 3671-3681 [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]  
  • Gerhard, R., Tatge, H., Genth, H., Thum, T., Borlak, J., Fritz, G., Just, I. (2005). Clostridium difficile Toxin A Induces Expression of the Stress-induced Early Gene Product RhoB. J. Biol. Chem. 280: 1499-1505 [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]  
  • Moulder, S. L., Mahany, J. J., Lush, R., Rocha-Lima, C., Langevin, M., Ferrante, K. J., Bartkowski, L. M., Kajiji, S. M., Noe, D. A., Paillet, S., Sullivan, D. M. (2004). A Phase I Open Label Study of the Farnesyltransferase Inhibitor CP-609,754 in Patients with Advanced Malignant Tumors. Clin. Cancer Res. 10: 7127-7135 [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]  
  • Nesterov, A., Nikrad, M., Johnson, T., Kraft, A. S. (2004). Oncogenic Ras Sensitizes Normal Human Cells to Tumor Necrosis Factor-{alpha}-Related Apoptosis-Inducing Ligand-Induced Apoptosis. Cancer Res. 64: 3922-3927 [Abstract] [Full Text]  
  • Sebti, S. M. (2003). Blocked Pathways: FTIs Shut Down Oncogene Signals. The Oncologist 8: 30-38 [Abstract] [Full Text]  
  • Adini, I., Rabinovitz, I., Sun, J. F., Prendergast, G. C., Benjamin, L. E. (2003). RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development. Genes Dev. 17: 2721-2732 [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]  
  • Ma, B. B.Y., Bristow, R. G., Kim, J., Siu, L. L. (2003). Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents. JCO 21: 2760-2776 [Abstract] [Full Text]  
  • Shi, Y., Gera, J., Hsu, J.-h., Van Ness, B., Lichtenstein, A. (2003). Cytoreductive Effects of Farnesyl Transferase Inhibitors on Multiple Myeloma Tumor Cells. Molecular Cancer Therapeutics 2: 563-572 [Abstract] [Full Text]  
  • Yang, H.-L., Pan, J.-X., Sun, L., Yeung, S.-C. J. (2003). p21 Waf-1 (Cip-1) Enhances Apoptosis Induced by Manumycin and Paclitaxel in Anaplastic Thyroid Cancer Cells. J. Clin. Endocrinol. Metab. 88: 763-772 [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]  
  • Sharma, S., Kemeny, N., Kelsen, D. P., Ilson, D., O'Reilly, E., Zaknoen, S., Baum, C., Statkevich, P., Hollywood, E., Zhu, Y., Saltz, L. B. (2002). A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan. Ann Oncol 13: 1067-1071 [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]  
  • 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]  
  • Pan, J., Xu, G., Yeung, S.-C. J. (2001). Cytochrome c Release Is Upstream to Activation of Caspase-9, Caspase-8, and Caspase-3 in the Enhanced Apoptosis of Anaplastic Thyroid Cancer Cells Induced by Manumycin and Paclitaxel. J. Clin. Endocrinol. Metab. 86: 4731-4740 [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]  
  • Xu, G., Pan, J., Martin, C., Yeung, S.-C. J. (2001). Angiogenesis Inhibition in the in Vivo Antineoplastic Effect of Manumycin and Paclitaxel against Anaplastic Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 86: 1769-1777 [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]  
  • 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 © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»