Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice.

Saı̈d M. Sebti,Gilles Favre,Anne Pradines,Jalila Adnane,Zhi Chen,Jiazhi Sun

doi:10.1074/jbc.c000145200

Abstract

Whereas the GTPase RhoA has been shown to promote proliferation and malignant transformation, the involvement of RhoB in these processes is not well understood. In this manuscript RhoB is shown to be a potent suppressor of transformation and human tumor growth in nude mice. In several human cancer cell lines, RhoA promotes focus formation whereas RhoB is as potent as the tumor suppressor p53 at inhibiting transformation in this assay. RhoB is both farnesylated (F) and geranylgeranylated (GG), and RhoB-F has been suggested as a target for the antitumor activity of farnesyltransferase inhibitors. Here we demonstrate that both RhoB-F and RhoB-GG inhibit anchorage-dependent and -independent growth, induce apoptosis, inhibit constitutive activation of Erk and insulin-like growth factor-1 stimulation of Akt, and suppress tumor growth in nude mice. The data demonstrate that RhoB is a potent suppressor of human tumor growth and that RhoB-F is not a target for farnesyltransferase inhibitors.

Highlights

Low molecular weight GTP/GDP-binding GTPases such as Ras and Rho transduce mitogenic and survival signals from cell surface receptor to the nucleus [1,2,3]
Ras triggers a complex set of signal transduction pathways. These include the phosphatidylinositol 3-kinase/Akt pathway believed to be critical for cell survival and the Raf/Mek/Erk kinase cascade that has been implicated in cell proliferation [1,2,3]
RhoB is an immediate early response gene that is induced by platelet-derived growth factor, transforming growth factor-␣, the non-receptor tyrosine kinase v-Src, and ultraviolet irradiation [3, 10, 11]

Summary

Introduction

Low molecular weight GTP/GDP-binding GTPases such as Ras and Rho transduce mitogenic and survival signals from cell surface receptor to the nucleus [1,2,3]. In several human cancer cell lines, RhoA promotes focus formation whereas RhoB is as potent as the tumor suppressor p53 at inhibiting transformation in this assay.

Results

Conclusion