Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice

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.

Farnesylated RhoB inhibits radiation-induced mitotic cell death and controls radiation-induced centrosome overduplication

“…13,18 Moreover, the role of RhoB in cell death mechanisms, and more precisely in apoptosis regulation, has been widely reported in fibroblasts and epithelial cells. 19,20 We demonstrated earlier that expression of the dominant negative form of RhoB, RhoBN19, in FGF-2-expressing HeLa cells 21 or in radioresistant U87 human glioma 7 dramatically reduced cell survival following irradiation of these two cell lines, but this effect was also apparent in U87 xenografts, 22 as previously shown using FTIs. 6,7 Furthermore, inhibiting RhoB in these radioresistant cell lines increased the percentage of cells undergoing mitotic cell death.…”

“…Ionizing radiation can induce apoptotic or mitotic cell death. The involvement of RhoB in apoptosis has already been described in cancer cells 20 or in cells exposed to DNA-damaging agents. In particular, Liu et al 19 have demonstrated that, in E1A transformed mouse embryo fibroblasts (MEF), RhoB loss was associated with resistance to DNA-damage-induced apoptosis.…”

In vivo restoration of RhoB expression leads to ovarian tumor regression

“…14,29 Numerous studies have indicated a repression of GTPase RhoB in a significant number of cancers including ovarian cancer. 7,14,16 Moreover, the ability of RhoB to inhibit the tumoral growth of many cancer cell lines both in vitro and in vivo 6,7 suggests that RhoB may play a tumor suppressor role. 5 Here, we examined whether in vivo restoration of RhoB expression in RhoB downregulated ovarian cancer cells would reverse malignancy.…”

“…Ectopic expression of RhoB inhibits tumor growth in vitro and in vivo and metastasis, and also inhibits oncogenic signaling. [5][6][7][8] Moreover, rhoBÀ/À transformed cells are very aggressive and RhoB knockout mice show increased sensitivity to chemically induced tumors. 9 Ectopic expression of RhoB induces apoptosis in some cell models, 8,10,11 whereas rhoBÀ/À cells show resistance to apoptosis induced by radiation and cytotoxic agents.…”

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

“…Recent evidence demonstrated that RhoB has tumor suppressive activity (Du and Prendergast, 1999;Chen et al, 2000;Fritz and Kaina, 2000;Liu et al, 2000). First, RhoB is induced as an early response of eucaryotic cells to genotoxic stress resulting in either a prolonged transient block to DNA replication or apoptosis (Fritz et al, 1995;Fritz et al, 1999).…”