Abstract
Farnesyl transferase inhibitors (FTIs) are a novel class of antitumor drugs that block the oncogenic activity of Ras. Because FTIs lack significant cell toxicity in vitro and in vivo, a significant question is how they cause tumor regression. We now report that FTIs are in fact potent activators of apoptosis in Ras-transformed cells if attachment to substratum is prevented. When cultured at high density or on polyHEMA, a nonadherent substrate, Ras- transformed cells exhibited massive DNA degradation and cell death within 24 h of treatment with the FTI L-739,749. Death was p53-independent and was inhibited by the apoptosis suppressor BCL-X(L). Furthermore, apoptosis was significantly attenuated by ectopic expression of a farnesyl-independent form of RhoB, a Rho protein previously implicated as a critical target for inhibition by FTIs. The findings suggest a link between FTIs and Rho- dependent adhesion signaling. Furthermore, our work indicates that FTIs revert cells to a state in which cell-substratum attachment is necessary for viability and suggests that apoptosis forms the basis for drug-induced tumor regression.
Original language | English (US) |
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Pages (from-to) | 708-713 |
Number of pages | 6 |
Journal | Cancer Research |
Volume | 57 |
Issue number | 4 |
State | Published - 1997 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research