RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors.

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