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The Wistar Institute [P. F. L., D. S., G. C. P.], Cell and Molecular Biology Graduate Group [P. F. L.], and Department of Genetics [G. C. P.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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-XL. 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.
1 Supported by NIH Grant CA65892 (to G. C. P.). P. F. L. is supported by a Medical Scientist Training Program Award from the University of Pennsylvania Medical School and by a fellowship from Merck Research Laboratories. G. C. P. is the recipient of an American Cancer Society Junior Faculty Award and is a Pew Scholar in the Biomedical Sciences.
2 To whom requests for reprints should be addressed, at The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268. Phone: (215) 898-3792; Fax: (215) 898-2205.
Received 9/10/96. Accepted 12/19/96.
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