A yeast-based genomic strategy highlights the cell protein networks altered by FTase inhibitor peptidomimetics

Here we used a yeast-based cellular assay to define the transcriptional changes consequent to FTI peptidomimetic administration in conditions that do not substantially change Ras membrane/cytosol distribution. Yeast and cancer cell lines were used to validate the results of the network analysis. The transcriptome of yeast cells treated with FTase inhibitor I was compared with that of untreated cells and with an isogenic strain genetically inhibited for FTase activity (Δram1). Cells treated with GGTI-298 were analyzed in a parallel study to validate the specificity of the FTI response. Network analysis, based on gene ontology criteria, identified a cell cycle gene cluster up-regulated by FTI treatment that has the Aurora A kinase IPL1 and the checkpoint protein MAD2 as hubs. Moreover, TORC1-S6K-downstream effectors were found to be down-regulated in yeast and mammalian FTI-treated cells. Notably only FTIs, but not genetic inhibition of FTase, elicited up-regulation of ABC/transporters.This work provides a view of how FTIs globally affect cell activity. It suggests that the chromosome segregation machinery and Aurora A association with the kinetochore as well as TORC1-S6K downstream effectors are among the ultimate targets affected by the transcriptional deregulation caused by FTI peptidomimetics. Moreover, it stresses the importance of monitoring the MDR response in patients treated with FTIs.Farnesyl transferase (FTase) and Geranylgeranyl transferase I (GGTase I) are heterodimeric enzymes that catalyze the transfer of C-15 or C-20 lipid moieties, respectively, to the C-terminal cysteine of proteins having CAAX motifs at their C-terminus, the last amino acid discriminating among the two enzyme substrates [1]. The observation that Ras oncoproteins require farnesylation for membrane binding and malignant activity led to the development of drugs targeting FTase. As FTase structure and function has been conserved throughout evolution, the first farnesyl transferase inhib