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| Geranylgeranylaled RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors |
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| Author(s): Du W, Prendergast GC |
| Source: CANCER RESEARCH Volume: 59 Issue: 21 Pages: 5492-5496 Published: NOV 1 1999 |
| Times Cited: 101 References: 52 |
| Abstract: 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 p21(WAF1) activation. Consistent with actions beyond G(1)-phase arrest, certain cell lines exhibited accumulation in G(2)-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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Prendergast, GC (reprint author), Wistar Inst, Philadelphia, PA 19104 USA |
Addresses:
1. Wistar Inst, Philadelphia, PA 19104 USA |
| Publisher: AMER ASSOC CANCER RESEARCH, PO BOX 11806, BIRMINGHAM, AL 35202 USA |
| Subject Category: Oncology |
| IDS Number: 252KG |
| ISSN: 0008-5472 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |