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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.


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