Inhibition of farnesyltransferase increases TGF beta type II receptor expression and enhances the responsiveness of human cancer cells to TGF beta

Several small GTPases of the Ras superfamily have been shown to antagonize TGF beta signaling in human tumor cell lines. Some of these GTPases are pos t-translationally modified by farnesylation, a lipid modification catalyzed by farnesyltransferase and required for the proteins to attach to membrane s and to function. In this study, we investigated the effect of the farnesy ltransferase inhibitor FTI-277 on TGF beta -regulated cell growth and trans cription. Treatment of the human pancreatic tumor cell line, Panc-1, with F TI-277 enhanced the ability of TGF beta to inhibit both anchorage-dependent and -independent tumor cell growth. FTI-277 also enhanced the ability of T GF beta to induce transcription, as measured by p3TP-lux reporter activity and collagen synthesis. The enhancement of TGF beta responses by FTI-277 co rrelated with the stimulation of transcription and protein expression of ty pe II TGF beta receptor (T beta RII). Consequently, FTI-277-treated cells e xhibited a higher level of TGF beta binding to its receptor. Thus, inhibiti on of protein farnesylation stimulates T beta RII expression, which leads t o increased TGF beta receptor binding and signaling as well as inhibition o f tumor cell growth and transformation.