Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors

Lackner, Mark R.; Kindt, Rachel M.; Carroll, Pamela M.; Brown, Katherine A.; Cancilla, Michael R.; Chen, Changyou; Silva, Heshani de; Franke, Yvonne; Guan, Bo; Heuer, Tim; Hung, Tak; Keegan, Kevin P.; Kim, Jae Pil; Manne, Veeraswamy; O’Brien, Carol; Parry, Dianne; Pérez-Villar, Juan J.; Reddy, Rajashekar K.; Xiao, Hong; Zhan, Hualin; Cockett, Mark I.; Plowman, Gregory D.; Fitzgerald, Kevin; Costa, Michael J.; Ross‐Macdonald, Petra

doi:10.1016/j.ccr.2005.03.024

Cited by 131 publications

(135 citation statements)

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“…The seven genes that were up-regulated within the refractory cohort were not obviously linked to chemotherapy resistance although RABGGTB, a potential target of farnesyl transferase inhibitors and bisphosphonates (Lackner et al, 2005;Roelofs et al, 2006) and POLE, a target for antimetabolite nucleosides (Miura & Izuta, 2004) might be of interest for further studies.…”

Section: Discussionmentioning

confidence: 99%

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

et al. 2008

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SummaryIn order to identify genes associated with primary chemotherapy‐resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B‐cell lymphoma (DLBCL), stage II–IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy‐nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM‐1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin‐3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

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Section: Discussionmentioning

confidence: 99%

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

et al. 2008

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“…Other examples of dual-specificity inhibitors include the Bristol-Myers Squibb compounds BMS1, BMS2, BMS3 and BMS4, which inhibit both PFT and PGGT-II (ref. 95 ). These compounds are strongly proapoptotic, which distinguishes them from other FTI compounds.…”

Section: Development Of Ftis As Cancer Therapeuticsmentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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“…Several nonRas targets such as RhoB and Rab geranylgeranyltransferase have been proposed (25,26). In addition, Akt inactivation appears to play a role in apoptosis induced by a subset of FTIs (5,27,28), although some studies have been unable to demonstrate this role (29 -31).…”

mentioning

confidence: 99%

The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells

Sun

Liu

Zou

et al. 2007

Journal of Biological Chemistry

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Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated lonafarnib-induced apoptosis, indicating that lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated lonafarnib-induced DR5 expression. These results thus indicate that lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to lonafarnib-induced apoptosis.Farnesyltransferase inhibitors (FTIs) 3 are a class of agents that suppress the farnesyltransferase enzyme to prevent farnesylation of certain proteins such as the Ras oncoprotein (1, 2). These agents inhibit proliferation and induce apoptosis in various cancer cell lines in culture or suppress the growth of xenografts in nude mice with limited toxicity (1, 2). In the clinic, FTIs are well tolerated and have some positive outcomes in certain settings such as hematological malignancies and breast cancer, although the response rates to FTIs alone are generally poor. When combined with other therapeutic agents or radiotherapy, FTIs exhibit some encouraging clinical responses (1, 2).Lonafarnib (LNF; also called SCH66336 and Sarasar), a nonpeptide tricyclic FTI, was one of the first FTIs to undergo clinical testing and to exhibit significant activity (3). In vitro, this agent, either alone or in combination with other therapeutic agents, inhibits the growth or induces apoptosis of several types of human cancer cells (4 -12). In animal models, LNF demonstrates potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin (12). When LNF is combined with other chemotherapeutic agents, enhanced anti...

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Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors

Cited by 131 publications

References 53 publications

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy‐refractory diffuse large B‐cell lymphoma

Therapeutic intervention based on protein prenylation and associated modifications

The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells

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