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

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Abstract
Several small GTPases of the Ras superfamily have been shown to antagonize TGFβ signaling in human tumor cell lines. Some of these GTPases are post-translationally modified by farnesylation, a lipid modification catalyzed by farnesyltransferase and required for the proteins to attach to membranes and to function. In this study, we investigated the effect of the farnesyltransferase inhibitor FTI-277 on TGFβ-regulated cell growth and transcription. Treatment of the human pancreatic tumor cell line, Panc-1, with FTI-277 enhanced the ability of TGFβ to inhibit both anchorage-dependent and -independent tumor cell growth. FTI-277 also enhanced the ability of TGFβ to induce transcription, as measured by p3TP-lux reporter activity and collagen synthesis. The enhancement of TGFβ responses by FTI-277 correlated with the stimulation of transcription and protein expression of type II TGFβ receptor (TβRII). Consequently, FTI-277-treated cells exhibited a higher level of TGFβ binding to its receptor. Thus, inhibition of protein farnesylation stimulates TβRII expression, which leads to increased TGFβ receptor binding and signaling as well as inhibition of tumor cell growth and transformation.

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