Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment

Peter F. Lebowitz, Daitoku Sakamuro, George C. Prendergast

Research output: Contribution to journalArticle

175 Scopus citations

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 languageEnglish (US)
Pages (from-to)708-713
Number of pages6
JournalCancer Research
Volume57
Issue number4
StatePublished - Mar 3 1997
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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