Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors.
Farnesyltransferase inhibitors (FTIs) are in clinical trials, but their mechanism of action is not fully understood. We have shown that FTI treatment rapidly elevates the level of geranylgeranylated RhoB in cells and that this event is sufficient to inhibit cell cycle transit and reverse malignant transformation without affecting normal cells. However, because these observations were made in rodent fibroblast models in which transformation was driven by defined genetic alterations, it remained to be established whether RhoB-GG was relevant to the antineoplastic effects of FTIs in human epithelial tumor cells with diverse genetic backgrounds. In this study, we show that elevated levels of RhoB-GG are sufficient to block the proliferation of FTI-sensitive but not FTI-resistant human carcinoma cells. RhoB-GG induced the cell cycle kinase inhibitor p21(WAF1) in a p53-dependent manner, similar to FTI treatment, but this event was dispensable because RhoB-GG could still inhibit the growth of p53-null cells that lacked p21WAF1 activation. Consistent with actions beyond G1-phase arrest, certain cell lines exhibited accumulation in G2-M phase or an increased apoptotic index in response to RhoB-GG. We concluded that RhoB-GG suppressed human tumor cell proliferation by more than one mechanism and that it promoted apoptosis as well as inhibited cell cycle transit in malignant epithelial cells. These findings suggest how FTIs suppress the growth of human tumor cells that lack Ras mutations.
Du
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The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Prendergast
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GC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051231:Farnesyltranstransferase; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism; D010957:Plasmids; D017368:Protein Prenylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020743:rhoB GTP-Binding Protein; D015032:Zinc