**4.2 Role of isoprenoid lipids, GTPases, and Rho in sarcomas**

Members of the Rho family of small GTPases are involved in important functions involved in malignant transformation and progression, like actin reorganization, cell motility, or cell-cell and cell-ECM [55]. Rho proteins are promising targets as a novel anticancer drug in several cancers [56] including sarcoma [28]. Rho GTPases localized at membranes become activated upon stimulation of cell surface receptors. So, Rho GEFs are often oncogenic, and the expression level of Rho GTPases frequently increases with malignancy. A possible drawback of isoprenylation inhibitors is their poor selectivity for individual Rho GTPases. High levels of RhoA and/or RhoC have been observed to indicate a poor prognosis [81]. In addition, RhoA is involved in tumor progression invasion [57] and RhoC in tumor invasion. Cell growth arrest and proliferation inhibition in osteosarcoma depend on GGPP prenylation, rather than FPP and farnesylation [19]. Similarly, treatment of NIH3T3 sarcoma cells with GGTI-298 or lovastatin stops the cell cycle [82]; but FTI-277 has no such effect. So, geranylgeranylated proteins play a critical role in the cell cycle [83]. Statin-induced apoptosis is also associated with changes in RhoA protein geranylgeranylation in human chondrosarcoma [41] and osteosarcoma cell lines. Besides, in osteosarcoma cells, simvastatin induced mevalonate-dependent apoptosis [30], mediated by the MAPK-RhoA-p42/p44-bcl-2 mechanism [28]; or by activation of AMPK and p38 MAPK [84]; or is associated with the RhoA/Stat1/bcl-2 signaling pathway [24, 30]. Inhibition of geranylation by statins is also responsible for apoptosis in sarcomas [85]. Thus, in osteosarcoma and chondrosarcoma cell lines [41], geranylgeranylation inhibition induces apoptosis, which can be restored by adding GGPP, but not FPP. Similar results have been observed after treating sarcomas with GGTI-298, but not with FTI-277. This different effect of isoprenoid lipids on sarcoma cells may be due to the fact that GGPP is derived from the condensation of FPP and isopentenyl pyrophosphate (IPP). Since IPP could not be synthesized in cells treated with simvastatin, FPP could not be converted into GGPP.
