Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

Abstract

The ability of Ras oncoproteins to cause malignant transformation requires their post-translational modi®ca-tions by prenyl groups. Because K-Ras can be both farnesylated and geranylgeranylated it is not known whether both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for suppressing human tumor growth in whole animals. In this paper we report that oncogenic Ras processing, MAP kinase activation and growth in nude mice are inhibited by the farnesyltransferase inhibitor FTI-276 in H-and N-Ras transformed NIH3T3 cells; whereas in K B -Ras transformed NIH3T3 cells both FTI-276 and the geranylgeranyltransferase I inhibitor GGTI-297 are required for inhibition. Furthermore, human lung A-549 and Calu-1 carcinoma cell lines were found to co-express H-, N-and K-Ras. In Calu-1 cells, the processing of H-and N-Ras is inhibited greatly by FTI-276 but only partially by GGTI-297 whereas K-Ras processing inhibition requires both FTI-276 and GGTI-297. In contrast, in A-549 cells the processing of H-and N-Ras is inhibited only by FTI-276 and K-Ras processing is resistant to co-treatment with FTI-276 and GGTI-297. Yet, the growth in nude mice of A-549 and Calu-1 xenografts, both of which express K-Ras mutations, is inhibited by FTI-276 (80% inhibition) and GGTI-297 (60%). Furthermore, FTI-276 inhibits tumor growth of NIH3T3 cells transformed by a form of oncogenic H-Ras that is exclusively geranylgeranylated and whose processing is resistant to this inhibitor. Taken together, the results demonstrate that both FTase and GGTase I inhibitors are required for inhibition of K-Ras processing but that each alone is su cient to suppress human tumor growth in nude mice.

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

“…Finally, RhoB expression was found to be very low in 130 human cancer cell lines (Wang et al, 2003), giving further support to RhoB tumor suppressive activity. FTIs and GGTIs were shown to be potent inhibitors of cell proliferation and tumor growth in various animal models (Kohl et al, 1994;Nagasu et al, 1995;Barrington et al, 1998;Liu et al, 1998;Sun et al, 1998;Hunt et al, 2000). However, the mechanism by which this occurs is not known (Prendergast, 2001;Sebti and Der, 2003).…”

“…Because prenylation is required for Ras and Rho protein-mediated oncogenesis, metastasis and invasiveness, we and others have designed CAAX peptidomimetics that are potent and selective inhibitors of FTase (FTIs) and GGTase I (GGTIs), respectively, as potential anticancer drugs (Sebti and Hamilton, 2000). FTIs and GGTIs are potent inhibitors of Ras and Rho processing, respectively, and suppress the growth of murine and human tumors in various animal models (Kohl et al, 1994;Nagasu et al, 1995;Barrington et al, 1998;Liu et al, 1998;Sun et al, 1998;Hunt et al, 2000). Recent investigations into the biological mechanisms that underlie FTI anti-transforming effects have raised questions about their exact mode of action (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003).…”

“…For example, there was no correlation between the Ras mutation status and reversal of transformation as some cancer cells that do not express oncogenic Ras were sensitive to FTI, and inversely, some cancer cells containing activated Ras were resistant to FTI (Cox and Der, 1997;Gibbs and Oliff, 1997;Sebti and Hamilton, 2000;Sebti and Der, 2003). In addition, in vitro and in vivo experiments have shown that K-Ras was geranylgeranylated in cells treated with FTIs (Rowell et al, 1997;Whyte et al, 1997;Sun et al, 1998). Thus, both FTase and GGTase I need to be inhibited to fully block K-Ras isoprenylation (Lerner et al, 1997).…”

The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells

“…12 To date, the majority of studies using prenylation inhibitors have focused on solid tumors, including lung, bladder, breast, and colon carcinomas. 11,[13][14][15] In this study, we examined the activity of prenylation inhibitors in myeloma cell lines with different Ras mutation status, using the CAAX peptidomimetics FTI-277 16 and GGTI-2166. 17 These inhibitors are structural analogues based on the tertiary structure of the CAAX tetrapeptide.…”

Farnesylthiosalicylic acid induces caspase activation and apoptosis in glioblastoma cells

“…[16][17][18] After synthesis, each form of Ras is prenylated in the cytoplasm via one of three different enzymes: farnesyl transferase (FTase) and geranylgeranyl transferases I and II (GGTase). [19][20][21] The prenylated Ras proteins are further methylated by prenylated protein methyltransferase (PPMT) before being anchored to a specific membrane 'acceptor site'. 22 The inhibitors (FTIs) of FTase and GGTase are in various stages of clinical trials and the results obtained with FTIs alone were disappointing.…”