Post-translational modifications with the lipids farnesyl or geranylgeranyl (together referred to as prenyl) are catalysed by farnesyltransferase (FT) or geranylgeranyltransferase 1 (GGT1) and are required for the cellular localization, function and cancer-causing activities of some proteins. Among the hundreds of proteins that are estimated to be prenylated most are either exclusively farnesylated (for example, HRAS and RAS homologue enriched in brain (RHEB)) or geranylgeranylated (for example, RHOA, RHOC, RALA and RALB); some are both farnesylated and geranylgeranylated (RHOB), and others are naturally farnesylated but become geranylgeranylated when FT is inhibited (for example, KRAS and NRAS).
These and other important observations prompted the design and development of inhibitors of FT (FTIs) and GGT1 (GGTIs) as potential anticancer drugs. Several FTIs have been tested clinically but only one GGTI has recently entered clinical trials.
Further validation of FT and GGT1 as anticancer drug targets was recently provided by genetic mouse models: conditional loss of FT and/or GGT1 hampers mutant KRAS-induced tumorigenesis and extends the lifespan of mice.
FTI treatment results in the reversal of several hallmarks of cancer, including mitotic arrest at prometaphase, induction of apoptosis, inhibition of anchorage-dependent and anchorage-independent growth, invasion, angiogenesis and tumour growth, as well as induction of tumour regression in animal models. These effects seem to be mediated by interference with aberrant signal transduction pathways such as RAF–MEK–ERK, PI3K–AKT, and other oncogenic and survival pathways.
GGTI treatment also results in the reversal of the cancer hallmarks mentioned above except that they block cells in the G1 phase of the cell cycle, and this seems to be owing to their ability to induce the accumulation of the cyclin-dependent kinase (CDK) inhibitors p21 and p27 and to inhibit CDKs and induce hypophosphorylation of RB. GGTI treatment also decreases the levels of phospho-AKT and survivin, and this seems to mediate their ability to induce apoptosis.
Although in preclinical models FTIs are highly effective as antitumour agents, in clinical trials limited efficacy was observed. This is primarily due to poor patient selection. This in turn is due to our lack of understanding of the mechanism of action of FTIs. In the future, a major effort must be dedicated to identifying the prenylated proteins the inhibition of which is responsible for the antitumour effects of PTIs. This will be of great value not only for enhancing our understanding of the mechanism of action of FTIs and GGTIs, but also for selecting patients whose tumours are addicted to specific prenylated proteins and who are more likely to respond to these agents. Recent advances in techniques to characterize the human prenylome are likely to accelerate achieving these crucial goals in the prenylation field.
Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyltransferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.
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Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).
Jackson, J. H. et al. Farnesol modification of Kirsten-ras exon 4B protein is essential for transformation. Proc. Natl Acad. Sci. USA 87, 3042–3046 (1990).
Bommi-Reddy, A. & Kaelin, W. G. Slaying RAS with a synthetic lethal weapon. Cell Res. 20, 119–121 (2010).
Van Cutsem, E. et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22, 1430–1438 (2004).
Rao, S. et al. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J. Clin. Oncol. 22, 3950–3957 (2004).
Blumenschein, G. et al. A randomized phase III trial comparing lonafarnib/carboplatin/paclitaxel versus carboplatin/paclitaxel (CP) in chemotherapy-naïve patients with advanced or metastatic non-small cell lung cancer. Lung Cancer 49, S30 (2005).
Harousseau, J. L. et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 114, 1166–1173 (2009). References 4–7 describe the results of Phase III clinical trials with lonafarnib or tipifarnib. Whether alone or in combination the FTIs failed to even slightly improve the outcome for patients with advanced NSCLC, advanced pancreatic cancer, advanced colon cancer or AML.
Adjei, A. A. et al. A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin. Cancer Res. 9, 2520–2526 (2003).
Siegel-Lakhai, W. S. et al. Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Br. J. Cancer 93, 1222–1229 (2005).
Sparano, J. A. et al. Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. J. Clin. Oncol. 24, 3013–3018 (2006).
Sparano, J. A. et al. Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin. Cancer Res. 15, 2942–2948 (2009). References 8–11 stand out from the bulk of clinical trials with FTIs in that they demonstrate that a combination of tipifarnib with chemotherapy can make a difference, even in solid advanced tumours.
Rowell, C. A., Kowalczyk, J. J., Lewis, M. D. & Garcia, A. M. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J. Biol. Chem. 272, 14093–14097 (1997).
Whyte, D. B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).
Lerner, E. C. et al. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15, 1283–1288 (1997).
Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. 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. Oncogene 16, 1467–1473 (1998). References 12–15 by three independent groups show that KRAS can escape FTI-mediated inhibition and remain fully functional through undergoing cross-prenylation by GGT1. As KRAS is the most frequently mutated human oncogene, this finding was disappointing as it meant that KRAS function could not be inhibited with FTIs.
Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).
Lim, K.-H. et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7, 533–545 (2005). References 16 and 17 show that exclusively geranylgeranylated RALA and RALB, which are downstream of RAS, may be more important for some human cancers than the RAF–MEK–ERK or PI3K–AKT pathways.
Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).
Hakem, A. et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 19, 1974–1979 (2005). References 18 and 19 provide evidence that the exclusively geranylgeranylated RHOC is not necessary for embryonic development but is essential for metastasis. These results, together with those of references 16 and 17, can be regarded as a major incentive for developing GGTIs to treat advanced cancers.
Qiu, R. G., Abo, A., McCormick, F. & Symons, M. Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. Mol. Cell. Biol. 17, 3449–3458 (1997).
Joyce, P. L. & Cox, A. D. Rac1 and Rac3 are targets for geranylgeranyltransferase I inhibitor-mediated inhibition of signaling, transformation, and membrane ruffling. Cancer Res. 63, 7959–7967 (2003).
Kissil, J. L. et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res. 67, 8089–8094 (2007).
Lobell, R. B. et al. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res. 61, 8758–8768 (2001).
O'Dwyer, P. J., Gallagher, M., Nguyen, B., Waddell, M. J. & Chiorean, E. G. Phase I accelerated dose-escalating safety and pharmacokinetic (PK) study of GGTI-2418, a novel geranylgeranyltransferase I inhibitor in patients with refractory solid tumors. Ann. Oncol. 21, ii42 (2010).
Raponi, M. et al. Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. Clin. Cancer Res. 13, 2254–2260 (2007).
Raponi, M. et al. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood 111, 2589–2596 (2008). References 25 and 26 have advanced approaches to correctly predict clinical outcome following FTI therapy. The authors have identified a signature two-gene expression ratio ( RASGRPS1/APTX ) as a predictor for the response to tipifarnib in patients with AML.
Yang, W., Urano, J. & Tamanoi, F. Protein farnesylation is critical for maintaining normal cell morphology and canavanine resistance in Schizosaccharomyces pombe. J. Biol. Chem. 275, 429–438 (2000).
Cox, A. D., Hisaka, M. M., Buss, J. E. & Der, C. J. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol. Cell. Biol. 12, 2606–2615 (1992).
Perez-Sala, D. Protein isoprenylation in biology and disease: general overview and perspectives from studies with genetically engineered animals. Front. Biosci. 12, 4456–4472 (2007).
Sebti, S. M. Protein farnesylation: implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell 7, 297–300 (2005).
Mijimolle, N. et al. Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development. Cancer Cell 7, 313–324 (2005).
Ohya, Y. et al. Yeast CAL1 is a structural and functional homologue to the DPR1 (RAM) gene involved in ras processing. J. Biol. Chem. 266, 12356–12360 (1991).
Therrien, M. et al. KSR, a novel protein kinase required for RAS signal transduction. Cell 83, 879–888 (1995).
Sjogren, A. K. et al. GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer. J. Clin. Invest. 117, 1294–1304 (2007). This article shows that targeted deletion of Ggt1 in the lung reduces Kras -driven tumour formation and increases the lifespan of mice with Kras -induced lung cancer.
Reid, T. S., Terry, K. L., Casey, P. J. & Beese, L. S. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J. Mol. Biol. 343, 417–433 (2004).
Yang, S. H. et al. Caution! Analyze transcripts from conditional knockout alleles. Transgenic Res. 18, 483–489 (2009).
Liu, M. et al. Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc. Natl Acad. Sci. USA 107, 6471–6476 (2010). This article demonstrates that concomitant conditional loss of both FT and GGT1 in mice effectively reduces Kras -induced lung carcinogenesis, and extends the lifespan of these mice considerably more than FT or GGT1 deficiency alone, suggesting that the simultaneous inhibition of FT and GGT1 may be therapeutically beneficial in cancer patients.
Sjogren, A. K. et al. Inactivating GGTase-I reduces disease phenotypes in a mouse model of K-RAS-induced myeloproliferative disease. Leukemia 25, 186–189 (2011).
Wang, T. et al. The p21(RAS) farnesyltransferase α subunit in TGF-β and activin signaling. Science 271, 1120–1122 (1996).
Kumar, A., Beresini, M. H., Dhawan, P. & Mehta, K. D. α-subunit of farnesyltransferase is phosphorylated in vivo: effect of protein phosphatase-1 on enzymatic activity. Biochem. Biophys. Res. Commun. 222, 445–452 (1996).
Kumar, A. & Mehta, K. D. p21ras farnesyltransferase α- and β ubunits are phosphorylated in PC-12 cells: TGF-β signaling pathway independent phosphorylation. Neurosci. Lett. 231, 143–146 (1997).
Goalstone, M., Carel, K., Leitner, J. W. & Draznin, B. Insulin stimulates the phosphorylation and activity of farnesyltransferase via the Ras-mitogen-activated protein kinase pathway. Endocrinology 138, 5119–5124 (1997).
Kim, K. W. et al. Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: cleavage of the common α subunit during apoptosis. Oncogene 20, 358–366 (2001).
Singh, J., Hamid, R. & Reddy, B. S. Dietary fish oil inhibits the expression of farnesyl protein transferase and colon tumor development in rodents. Carcinogenesis 19, 985–989 (1998).
Caruso, M. G. et al. Increased farnesyltransferase activity in human colorectal cancer: relationship with clinicopathological features and K-ras mutation. Scand. J. Gastroenterol. 38, 80–85 (2003).
Lantry, L. E. et al. Chemopreventive efficacy of promising farnesyltransferase inhibitors. Exp. Lung Res. 26, 773–790 (2000).
Zhang, Z. et al. Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J. mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Oncogene 22, 6257–6265 (2003).
Lerner, E. C. et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J. Biol. Chem. 270, 26802–26806 (1995).
Jiang, K. et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 20, 139–148 (2000).
Sun, S. Y., Zhou, Z., Wang, R., Fu, H. & Khuri, F. R. The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt. Cancer Biol. Ther. 3, 1092–1098; discussion 1099–1101 (2004).
Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res. 55, 4243–4247 (1995).
Mangues, R. et al. Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res. 58, 1253–1259 (1998).
Omer, C. A. et al. Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Cancer Res. 60, 2680–2688 (2000).
Crespo, N. C., Ohkanda, J., Yen, T. J., Hamilton, A. D. & Sebti, S. M. The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J. Biol. Chem. 276, 16161–16167 (2001).
Crespo, N. C. et al. The farnesyltransferase inhibitor, FTI-2153, inhibits bipolar spindle formation during mitosis independently of transformation and Ras and p53 mutation status. Cell Death Differ. 9, 702–709 (2002).
Ashar, H. R. et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J. Biol. Chem. 275, 30451–30457 (2000).
Hussein, D. & Taylor, S. S. Farnesylation of Cenp-F is required for G2/M progression and degradation after mitosis. J. Cell Sci. 115, 3403–3414 (2002).
Wang, J., Kirby, C. E. & Herbst, R. The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. J. Biol. Chem. 277, 46659–46668 (2002).
Sepp-Lorenzino, L. & Rosen, N. A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells. J. Biol. Chem. 273, 20243–20251 (1998).
Reuveni, H., Klein, S. & Levitzki, A. The inhibition of Ras farnesylation leads to an increase in p27Kip1 and G1 cell cycle arrest. Eur. J. Biochem. 270, 2759–2772 (2003).
Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995). Using transgenic mice expressing mutant HRAS in the mammary glands, this is the first demonstration that FTIs cause persistent tumour regression in vivo.
Barrington, R. E. et al. A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol. Cell. Biol. 18, 85–92 (1998).
Lebowitz, P. F., Sakamuro, D. & Prendergast, G. C. Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment. Cancer Res. 57, 708–713 (1997).
Suzuki, N., Urano, J. & Tamanoi, F. Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells. Proc. Natl Acad. Sci. USA 95, 15356–15361 (1998).
Oh, S. H., Jin, Q., Kim, E. S., Khuri, F. R. & Lee, H. Y. Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. Clin. Cancer Res. 14, 1581–1589 (2008).
Zhang, B., Prendergast, G. C. & Fenton, R. G. Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression. Cancer Res. 62, 450–458 (2002).
Takada, Y., Khuri, F. R. & Aggarwal, B. B. Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-κB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-κB-regulated gene expression and up-regulation of apoptosis. J. Biol. Chem. 279, 26287–26299 (2004).
Lackner, M. R. et al. Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors. Cancer Cell 7, 325–336 (2005).
Han, J. Y. et al. Hypoxia-inducible factor 1α and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer. J. Natl. Cancer Inst. 97, 1272–1286 (2005).
Cohen-Jonathan, E. et al. The farnesyltransferase inhibitor L744, 832 reduces hypoxia in tumors expressing activated H-ras. Cancer Res. 61, 2289–2293 (2001).
Delmas, C. et al. The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clin. Cancer Res. 9, 6062–6068 (2003).
Kim, C. K. et al. The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways. Mol. Pharmacol. 78, 142–150 (2010).
Bernhard, E. J. et al. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Cancer Res. 56, 1727–1730 (1996).
Moasser, M. M. et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc. Natl Acad. Sci. USA 95, 1369–1374 (1998).
Basso, A. D. et al. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280, 31101–31108 (2005).
Adjei, A. A., Davis, J. N., Bruzek, L. M., Erlichman, C. & Kaufmann, S. H. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin. Cancer Res. 7, 1438–1445 (2001).
Zheng, H. et al. Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 297, 117–125 (2010). In this paper, the response to FTIs was correlated to the expression levels of RHEB in human lung tumour tissue and cell lines.
Russo, P., Malacarne, D., Falugi, C., Trombino, S. & O'Connor, P. M. RPR-115135, a farnesyltransferase inhibitor, increases 5-FU- cytotoxicity in ten human colon cancer cell lines: role of p53. Int. J. Cancer 100, 266–275 (2002).
Brassard, D. L. et al. Inhibitors of farnesyl protein transferase and MEK1, 2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras. Exp. Cell Res. 273, 138–146 (2002).
Edamatsu, H., Gau, C. L., Nemoto, T., Guo, L. & Tamanoi, F. Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene 19, 3059–3068 (2000).
Hoover, R. R., Mahon, F. X., Melo, J. V. & Daley, G. Q. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 100, 1068–1071 (2002).
Liu, M. et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res. 58, 4947–4956 (1998).
Shi, B. et al. The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo. Cancer Chemother. Pharmacol. 46, 387–393 (2000).
Sun, J. et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res. 59, 4919–4926 (1999).
Berndt, N. et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 17, 1795–1804 (2010).
Balasis, M. E. et al. Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant tumor regression in ErbB2 transgenic mice. Clin. Cancer Res. 17, 2852–2862 (2011).
Marcus, A. I. et al. The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res. 65, 3883–3893 (2005).
Marcus, A. I. et al. Farnesyltransferase inhibitors reverse taxane resistance. Cancer Res. 66, 8838–8846 (2006).
Zhou, J. et al. The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. J. Biol. Chem. 284, 9648–9655 (2009).
Vogt, A., Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J. Biol. Chem. 272, 27224–27229 (1997).
Sun, J. et al. The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. J. Biol. Chem. 274, 6930–6934 (1999).
Kazi, A. et al. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol. Cell. Biol. 29, 2254–2263 (2009). This paper demonstrates that the antitumour activity of GGTI-2417 and GGTI-2418 depends on stabilizing p27 via blocking its phosphorylation at Thr187. In vivo , GGTI-2418 prevents human breast tumour growth in nude mice and causes breast tumour regression in MMTV-Erbb2 transgenic mice.
Watanabe, M. et al. Inhibitors of protein geranylgeranyltransferase I and Rab geranylgeranyltransferase identified from a library of allenoate-derived compounds. J. Biol. Chem. 283, 9571–9579 (2008).
Lu, J. et al. In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol. Cancer Ther. 8, 1218–1226 (2009).
Dan, H. C. et al. Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. Oncogene 23, 706–715 (2004).
Chen, S. et al. Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol. Cancer 9, 23 (2010).
McGuire, T. F., Qian, Y., Vogt, A., Hamilton, A. D. & Sebti, S. M. Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation. J. Biol. Chem. 271, 27402–27407 (1996).
Falsetti, S. C. et al. Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Mol. Cell. Biol. 27, 8003–8014 (2007).
Peterson, Y. K., Kelly, P., Weinbaum, C. A. & Casey, P. J. A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J. Biol. Chem. 281, 12445–12450 (2006).
Peterson, Y. K., Wang, X. S., Casey, P. J. & Tropsha, A. Discovery of geranylgeranyltransferase-I inhibitors with novel scaffolds by the means of quantitative structure-activity relationship modeling, virtual screening, and experimental validation. J. Med. Chem. 52, 4210–4220 (2009).
Zujewski, J. et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J. Clin. Oncol. 18, 927–941 (2000). This is, to our knowledge, the first published report of a clinical trial with an FTI (tipifarnib).
Lobell, R. B. et al. Preclinical and clinical pharmacodynamic assessment of L-778, 123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol. Cancer Ther. 1, 747–758 (2002).
Kauh, J. et al. Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies. Cancer 117, 4049–4059 (2011).
Sepp-Lorenzino, L. et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 55, 5302–5309 (1995).
End, D. W. et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 61, 131–137 (2001).
Kurzrock, R. et al. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood 102, 4527–4534 (2003).
Kohl, N. E. et al. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc. Natl Acad. Sci. USA 91, 9141–9145 (1994).
Tee, A. R., Manning, B. D., Roux, P. P., Cantley, l.C. & Blenis, J. Turberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).
Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).
Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumor suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).
Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).
Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002).
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).
Castro, A. F., Rebhun, J. F., Clark, G. J. & Quilliam, L. A. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 278, 32493–32496 (2003).
Tabancay, A. P. et al. Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S76K. J. Biol. Chem. 278, 39921–39930 (2003).
Patel, P. H. et al. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J. Cell Sci. 116, 3601–3610 (2003). This paper shows that RHEB is required for cell growth (and cell cycle progression).
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702–713 (2005).
Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007).
Gromov, P. S., Madsen, P., Tomerup, N. & Celis, J. E. A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb. FEBS Lett. 377, 221–226 (1995).
Mavrakis, K. J. et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev. 22, 2178–2188 (2008). In this paper, RHEB was identified as a factor capable of enhancing lymphomagenesis in the E μ- Myc transgenic mouse. Importantly, inhibition of RHEB farnesylation by FTI-277 was identified as a major factor contributing to the antitumour effect of the FTI, suggesting that in lymphomas, and perhaps other haematological malignancies, RHEB is an important target for FTIs.
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).
Pan, J. et al. Autophagy induced by farnesyltransferase inhibitors in cancer cells. Cancer Biol. Ther. 7, 1679–1684 (2008).
Du, W., Lebowitz, P. F. & Prendergast, G. C. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol. Cell. Biol. 19, 1831–1840 (1999).
Du, W. & Prendergast, G. C. Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. 59, 5492–5496 (1999).
Mazières, J. et al. Geranylgeranylated, but not farnesylated, RhoB suppresses Ras transformation of NIH-3T3 cells. Exp. Cell Res. 304, 354–364 (2005).
Chen, Z. et al. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J. Biol. Chem. 275, 17974–17978 (2000).
Adnane, J., Muro-Cacho, C., Mathews, L., Sebti, S. M. & Munoz-Antonia, T. Suppression of rho B expression in invasive carcinoma from head and neck cancer patients. Clin. Cancer Res. 8, 2225–2232 (2002).
Forget, M. A. et al. The expression of rho proteins decreases with human brain tumor progression: potential tumor markers. Clin. Exp. Metastasis 19, 9–15 (2002).
Mazières, J. et al. Loss of RhoB expression in human lung cancer progression. Clin. Cancer Res. 10, 2742–2750 (2004).
Lebowitz, P. F., Casey, P. J., Prendergast, G. C. & Thissen, J. A. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J. Biol. Chem. 272, 15591–15594 (1997).
Armstrong, S. A., Hannah, V. C., Goldstein, J. L. & Brown, M. S. CAAX geranylgeranyl transferase transfers farnesyl as efficiently as geranylgeranyl to RhoB. J. Biol. Chem. 270, 7864–7868 (1995).
Delarue, F. L. et al. Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Oncogene 26, 633–640 (2007).
Liu, A., Du, W., Liu, J. P., Jessell, T. M. & Prendergast, G. C. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105–6113 (2000).
Xu, F. et al. The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice. Cancer Res. 60, 4913–4920 (2000).
Finlin, B. S. et al. RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J. Biol. Chem. 276, 42259–42267 (2001).
Hamaguchi, M. et al. DBC2, a candidate for a tumor suppressor gene involved in breast cancer. Proc. Natl Acad. Sci. USA 99, 13647–13652 (2002).
Ellis, C. A. et al. Rig is a novel Ras-related protein and potential neural tumor suppressor. Proc. Natl Acad. Sci. USA 99, 9876–9881 (2002).
Elam, C. et al. RRP22 is a farnesylated, nucleolar, ras-related protein with tumor suppressor potential. Cancer Res. 65, 3117–3125 (2005).
Boyartchuk, V. L., Ashby, M. N. & Rine, J. Modulation of Ras and α-factor function by carboxyl-terminal proteolysis. Science 275, 1796–1800 (1997).
Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004).
Linder, M. E. & Deschenes, R. J. Palmitoylation: policing protein stability and traffic. Nature Rev. Mol. Cell Biol. 8, 74–84 (2007).
Bergo, M. O. et al. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol. 22, 171–181 (2002).
Wang, M. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene 29, 4959–4970 (2010).
Forget, M. A., Desrosiers, R. R., Gingras, D. & Beliveau, R. Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes. Biochem. J. 361, 243–254 (2002).
Bivona, T. G. et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481–493 (2006). This article highlights a long neglected aspect of KRAS regulation, namely phosphorylation of KRAS at Ser181 and its functional consequences: PKC-mediated phosphorylation at this site, which is located within the polybasic region of the KRAS C terminus, converts KRAS from an oncogenic protein into a pro-apoptotic protein.
Rundell, C. J., Repellin, C. E. & Yarwood, S. J. Protease inhibitors prevent the protein kinase A-dependent loss of Rap1 GTPase from the particulate fraction of COS1 cells. Biochem. Biophys. Res. Commun. 315, 1077–1081 (2004).
Lang, P. et al. Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J. 15, 510–519 (1996).
Fitzgerald, M. L. & Reed, G. L. Rab6 is phosphorylated in thrombin-activated platelets by a protein kinase C-dependent mechanism: effects on GTP/GDP binding and cellular distribution. Biochem. J. 342, 353–360 (1999).
Riento, K. et al. RhoE function is regulated by ROCK I-mediated phosphorylation. EMBO J. 24, 1170–1180 (2005).
Sablina, A. A. et al. The tumor suppressor PP2A Aβ regulates the RalA GTPase. Cell 129, 969–982 (2007).
Lim, K. H. et al. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Mol. Cell. Biol. 30, 508–523 (2010). References 150 and 151 demonstrate that the transforming activity of RALA not only depends on prenylation, but also on phosphorylation at Ser194, which is controlled by aurora kinase A and PP2A. These findings may pave the way for new therapeutic opportunities, such as combining GGTIs with aurora kinase inhibitors.
Kwon, T., Kwon, D. Y., Chun, J., Kim, J. H. & Kang, S. S. Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1. J. Biol. Chem. 275, 423–428 (2000).
Tillement, V. et al. Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp. Cell Res. 314, 2811–2821 (2008).
Zheng, M. et al. Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nature Cell Biol. 13, 263–272 (2011).
Sarthy, A. V. et al. Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells. Mol. Cancer Ther. 6, 269–276 (2007).
Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).
Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–834 (2009).
Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009).
Singh, A. et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 15, 489–500 (2009).
Puyol, M. et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63–73 (2010). References 155–160 are particularly important as they identify novel promising targets for cancer patients whose tumours depend on KRAS for survival. Importantly, the four protein kinases identified are not essential for the survival of normal cells, but their loss of function in combination with activated KRAS is synthetically lethal. Reference 159 also emphasizes the point that not all KRAS-mutant cell lines are addicted to KRAS, suggesting that in a subset of tumours, KRAS may not be a suitable target.
Williams, J. P. et al. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Mol. Cell. Biol. 26, 1170–1182 (2006). This paper provides evidence that RAS-dependent transformation requires the presence of functional RB, a major tumour suppressor. Although this study uses murine fibroblasts, its findings may explain the fact that activating mutations of RAS and inactivating mutations of RB rarely occur together in human cancers.
Filmus, J. et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627–3633 (1994).
Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
Kaye, F. J. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene 21, 6908–6914 (2002).
Maurer-Stroh, S. et al. Towards complete sets of farnesylated and geranylgeranylated proteins. PLoS Comp. Biol. 3, e66 (2007). More than 100 proteins have been experimentally confirmed to undergo prenylation, but the exact size of the prenylome is unknown. This paper describes methods to better predict whether a potentially prenylatable protein is a substrate for FT, GGT1 or GGT2. These take into account the requirement for specific residues within the CaaX box, evolutionary conservation of the prenylation motif across phyla and physicochemical constraints extending up to 11 residues upstream of the prenylatable Cys.
Lane, K. T. & Beese, L. S. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J. Lipid Res. 47, 681–699 (2006).
Berndt, N. & Sebti, S. M. Measuring protein farnesylation and geranylgeranylation and using prenyltransferase inhibitors as chemical probes and anticancer agents. Nature Protoc. (in the press).
Kho, Y. et al. A tagging-via-substrate technology for detection and proteomics of farnesylated proteins. Proc. Natl Acad. Sci. USA 101, 12479–12484 (2004).
Troutman, J. M., Roberts, M. J., Andres, D. A. & Spielmann, H. P. Tools to analyze protein farnesylation in cells. Bioconjug. Chem. 16, 1209–1217 (2005).
Nguyen, U. T. et al. Analysis of the eukaryotic prenylome by isoprenoid affinity tagging. Nature Chem. Biol. 5, 227–235 (2009).
Onono, F. O. et al. A tagging-via-substrate approach to detect the farnesylated proteome using two-dimensional electrophoresis coupled with Western blotting. Mol. Cell. Proteomics 9, 742–751 (2010).
Chan, L. N. et al. A novel approach to tag and identify geranylgeranylated proteins. Electrophoresis 30, 3598–3606 (2009).
Degraw, A. J. et al. Evaluation of alkyne-modified isoprenoids as chemical reporters of protein prenylation. Chem. Biol. Drug Des. 76, 460–471 (2010). References 168–173 considerably advance our abilities to describe the effects of PTIs on the entire prenylome rather than just individual proteins. This is needed to identify prenylated proteins the inhibition of which contributes to the antitumour effects of PTIs.
Willumsen, B. M., Christensen, A., Hubbert, N. L., Papageorge, A. G. & Lowy, D. R. The p21 ras C-terminus is required for transformation and membrane association. Nature 310, 583–586 (1984).
Willumsen, B. M., Norris, K., Papageorge, A. G., Hubbert, N. L. & Lowy, D. R. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J. 3, 2581–2585 (1984). Although when references 174 and 175 were published it was unknown that RAS is farnesylated, these studies are important as they demonstrated that the C terminus of RAS is essential for both its membrane binding and its transforming activity.
Seabra, M. C., Reiss, Y., Casey, P. J., Brown, M. S. & Goldstein, J. L. Protein farnesyltransferase and geranylgeranyltransferase share a common α subunit. Cell 65, 429–434 (1991).
Zhang, F. L. et al. cDNA cloning and expression of rat and human protein geranylgeranyltransferase type-I. J. Biol. Chem. 269, 3175–3180 (1994).
Park, H. W., Boduluri, S. R., Moomaw, J. F., Casey, P. J. & Beese, L. S. Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science 275, 1800–1804 (1997).
Huang, C. C., Casey, P. J. & Fierke, C. A. Evidence for a catalytic role of zinc in protein farnesyltransferase. Spectroscopy of Co2+-farnesyltransferase indicates metal coordination of the substrate thiolate. J. Biol. Chem. 272, 20–23 (1997).
Zhang, F. L. & Casey, P. J. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269 (1996).
Carboni, J. M. et al. Farnesyltransferase inhibitors are inhibitors of Ras but not R-Ras2/TC21, transformation. Oncogene 10, 1905–1913 (1995).
Moores, S. L. et al. Sequence dependence of protein isoprenylation. J. Biol. Chem. 266, 14603–14610 (1991).
Boutin, J. A. et al. Chromatographic assay and peptide substrate characterization of partially purified farnesyl- and geranylgeranyltransferases from rat brain cytosol. Arch. Biochem. Biophys. 354, 83–94 (1998).
Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003).
Young, S. G., Fong, L. G. & Michaelis, S. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria-new evidence suggesting that protein farnesylation could be important for disease pathogenesis. J. Lipid Res. 46, 2531–2558 (2005).
Mallampalli, M. P., Huyer, G., Bendale, P., Gelb, M. H. & Michaelis, S. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 102, 14416–14421 (2005).
Toth, J. I. et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc. Natl Acad. Sci. USA 102, 12873–12878 (2005).
Yang, S. H. et al. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc. Natl Acad. Sci. USA 102, 10291–10296 (2005).
Fong, L. G. et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311, 1621–1623 (2006).
Yang, S. H. et al. Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria. J. Lipid Res. 51, 400–405 (2010).
Work, L. M. et al. Short-term local delivery of an inhibitor of Ras farnesyltransferase prevents neointima formation in vivo after porcine coronary balloon angioplasty. Circulation 104, 1538–1543 (2001).
Finder, J. D. et al. Inhibition of protein geranylgeranylation causes a superinduction of nitric-oxide synthase-2 by interleukin-1β in vascular smooth muscle cells. J. Biol. Chem. 272, 13484–13488 (1997).
Eastman, R. T., Buckner, F. S., Yokoyama, K., Gelb, M. H. & Van Voorhis, W. C. Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation. J. Lipid Res. 47, 233–240 (2006).
Carrico, D. et al. In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability. Bioorg. Med. Chem. 12, 6517–6526 (2004).
Nallan, L. et al. Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J. Med. Chem. 48, 3704–3713 (2005).
Yokoyama, K., Gillespie, J. R., Van Voorhis, W. C., Buckner, F. S. & Gelb, M. H. Protein geranylgeranyltransferase-I of Trypanosoma cruzi. Mol. Biochem. Parasitol. 157, 32–43 (2008).
Bordier, B. B. et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J. Clin. Invest. 112, 407–414 (2003).
Walters, C. E. et al. Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J. Immunol. 168, 4087–4094 (2002).
Coxon, F. P. et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J. Bone Miner. Res. 15, 1467–1476 (2000).
Kucich, U. et al. Requirement for geranylgeranyl transferase I and acyl transferase in the TGF-β-stimulated pathway leading to elastin mRNA stabilization. Biochem. Biophys. Res. Commun. 252, 111–116 (1998).
Kamiya, Y., Sakurai, A., Tamura, S. & Takahashi, N. Structure of rhodotorucine A, a novel lipopeptide, inducing mating tube formation in Rhodosporidium toruloides. Biochem. Biophys. Res. Commun. 83, 1077–1083 (1978).
Der, C. J., Krontiris, T. G. & Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes or Harvey and Kirsten sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 3637–3640 (1982).
Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474–478 (1982).
Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985).
Powers, S. et al. RAM, a gene of yeast required for a functional modification of RAS proteins and for production of mating pheromone a-factor. Cell 47, 413–422 (1986).
Wolda, S. L. & Glomset, J. A. Evidence for modification of lamin B by a product of mevalonic acid. J. Biol. Chem. 263, 5997–6000 (1988).
Farnsworth, C. C., Wolda, S. L., Gelb, M. H. & Glomset, J. A. Human lamin B contains a farnesylated cysteine residue. J. Biol. Chem. 264, 20422–20429 (1989).
Casey, P. J., Solski, P. A., Der, C. J. & Buss, J. E. p21ras is modified by a farnesyl isoprenoid. Proc. Natl Acad. Sci. USA 86, 8323–8327 (1989).
Hancock, J. F., Magee, A. I., Childs, J. E. & Marshall, C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57, 1167–1177 (1989).
Rilling, H. C., Breunger, E., Epstein, W. W. & Crain, P. F. Prenylated proteins: the structure of the isoprenoid group. Science 247, 318–320 (1990).
Farnsworth, C. C., Gelb, M. H. & Glomset, J. A. Identification of geranylgeranyl-modified proteins in HeLa cells. Science 247, 320–322 (1990).
Yamane, H. K. et al. Brain G protein γ subunits contain an all-trans-geranylgeranylcysteine methyl ester at their carboxyl termini. Proc. Natl Acad. Sci. USA 87, 5868–5872 (1990).
Mumby, S. M., Casey, P. J., Gilman, A. G., Gutowski, S. & Sternweis, P. C. G protein γ subunits contain a 20-carbon isoprenoid. Proc. Natl Acad. Sci. USA 87, 5873–5877 (1990).
Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J. & Brown, M. S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81–88 (1990).
Kitten, G. T. & Nigg, E. A. The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2. J. Cell Biol. 113, 13–23 (1991).
Kohl, N. E. et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260, 1934–1937 (1993).
Garcia, A. M., Rowell, C., Ackermann, K., Kowalczyk, J. J. & Lewis, M. D. Peptidomimetic inhibitors of Ras farnesylation and function in whole cells. J. Biol. Chem. 268, 18415–18418 (1993).
Nigam, M., Seong, C. M., Qian, Y., Hamilton, A. D. & Sebti, S. M. Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics. J. Biol. Chem. 268, 20695–20698 (1993).
James, G. L. et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 260, 1937–1942 (1993).
Gibbs, J. B. et al. Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo. J. Biol. Chem. 268, 7617–7620 (1993).
Hara, M. et al. Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc. Natl Acad. Sci. USA 90, 2281–2285 (1993).
This work was partially supported by US National Institutes of Health grants CA067771 and CA098473 to S.M.S.
S.M.S. and A.D.H. are inventors of GGTI-2418.
Compound structures and in vitro properties (PDF 573 kb)
Effects of PTIs in intact cells (PDF 216 kb)
Effects of PTIs in vivo (PDF 211 kb)
Clinical trials with farnesyltransferase inhibitors (PDF 375 kb)
Clinical trials with combinations including FTIs (PDF 229 kb)
Targeting KRAS-dependent tumours by exploiting synthetic lethality. (PDF 290 kb)
One of two types of prenylation. This involves the transfer of a farnesyl moiety to the cysteine of the C-terminal CaaX box of the target protein. Catalysed by farnesyltransferase.
This prenylation is catalysed by geranylgeranyltransferase 1 (GGT1) or GGT2. GGT1 transfers a geranylgeranyl moiety to the cysteine of the C-terminal CaaX box, and GGT2 acts on the cysteines of C-terminal CXC or CC motifs.
Also known as isoprenylation. An irreversible post-translational modification of proteins consisting of the covalent attachment of an isoprenyl lipid to a cysteine within four residues of the C terminus.
A universal and irreversible co-translational modification of proteins involving the covalent attachment of a myristoyl group to an N-terminal amino acid of a nascent polypeptide. It is important for membrane targeting of the modified protein.
- CaaX motif
This refers to the last four C-terminal amino acids that serve as a recognition motif for farnesyltransferase or geranylgeranyltransferase 1.C (cysteine) is the amino acid being modified, a is an aliphatic residue and X is any residue.
- Intimal hyperplasia
The thickening of the innermost layer of a blood vessel as a complication of a reconstruction procedure or endarterectomy. It is the universal response of a vessel to injury and is an important reason for late bypass graft failure, particularly in vein and synthetic vascular grafts.
A new or thickened layer of arterial intima (innermost layer of an artery or a vein) formed especially on a prosthesis or in atherosclerosis by migration and proliferation of cells from the media.
A post-translational modification, consisting of the covalent attachment of fatty acids to cysteine residues of membrane proteins, thought to further enhance membrane anchoring of previously prenylated proteins. In contrast to prenylation and myristoylation, it is reversible.
The subset of proteins in a cell or organism that is modified by prenylation.
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Berndt, N., Hamilton, A. & Sebti, S. Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11, 775–791 (2011). https://doi.org/10.1038/nrc3151
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