farnesyl-pyrophosphate and Neoplasms

Dysregulation of isoprenoid biosynthesis is implicated in numerous biochemical disorders that play a role in the onset and/or progression of age-related diseases, such as hypercholesterolemia, osteoporosis, various cancers, and neurodegeneration. The mevalonate metabolic pathway is responsible for the biosynthesis of the two key isoprenoid metabolites, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational prenylation of various proteins, including the small GTP-binding proteins (GTPases), with either FPP or GGPP is vital for proper localization and activation of these proteins. Prenylated GTPases play a critical role in cell signaling, proliferation, cellular plasticity, oncogenesis, and cancer metastasis. Pre-clinical and clinical studies strongly suggest that inhibition of protein prenylation can be an effective treatment for non-skeletal cancers. In this review, we summarize the most recent drug discovery efforts focusing on blocking protein farnesylation and/or geranylgeranylation and the biochemical and structural data available in guiding the current on-going studies in drug discovery. Furthermore, we provide a summary on the biochemical association between disruption of protein prenylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) signaling, and cancer.

Topics: Animals; Antineoplastic Agents; Biosynthetic Pathways; Drug Discovery; Enzyme Inhibitors; Farnesyltranstransferase; Geranyltranstransferase; Humans; Mevalonic Acid; Models, Molecular; Neoplasms; Polyisoprenyl Phosphates; Protein Prenylation; Sesquiterpenes

The cholesterol biosynthesis pathway, also referred to as the mevalonate (MVA) pathway, is responsible for the biosynthesis of two key isoprenoids: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational modification of small GTPases by FPP and GGPP has captured much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) catalyzes the conversion of HMG-CoA to MVA, and is the rate-limiting step in the biosynthesis of cholesterol. Statins are HMGCR inhibitors that are used extensively in the treatment of hypercholesterolemia. Inhibitors of the MVA pathway exhibit anti-tumor effects and may reduce cancer incidence and cancer-related mortality in humans. In this review, we will focus on the mevalonate cascade and its regulation in cholesterol metabolism as well as polymorphisms of the MVA cascade in cancer development, infectious and cardiovascular disease (CVD).

Topics: Acyl Coenzyme A; Animals; Cardiovascular Diseases; Cholesterol; GTP Phosphohydrolases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infections; Mevalonic Acid; Neoplasms; Polyisoprenyl Phosphates; Sesquiterpenes; Signal Transduction

Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor onto cell membranes and cannot induce this transformation. Posttranslational modification and plasma membrane association of mutant Ras is necessary for this transforming activity. Since its identification, the enzyme protein farnesyltransferase (FTase) that catalyzes the first and essential step of the three Ras-processing steps has emerged as the most promising target for therapeutic intervention. FTase has been implicated as a potential target in inhibiting the prenylation of a variety of proteins, thus in controlling varied disease states (e.g. cancer, neurofibromatosis, restenosis, viral hepatitis, bone resorption, parasitic infections, corneal inflammations, and diabetes) associated with prenyl modifications of Ras and other proteins. Furthermore, it has been suggested that FTase inhibitors indirectly help in inhibiting tumors via suppression of angiogenesis and induction of apoptosis. Major milestones have been achieved with small-molecule FTase inhibitors that show efficacy without toxicity in vitro, as well as in mouse models bearing ras-dependent tumors. With the determination of the crystal structure of mammalian FTase, existent leads have been fine-tuned and new potent molecules of diverse structural classes have been designed. A few of these molecules are currently in the clinic, with at least three drug candidates in Phase II studies and one in Phase III. This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic.

Topics: Alkyl and Aryl Transferases; Angiogenesis Inducing Agents; Animals; Antineoplastic Agents; Apoptosis; Cell Membrane; Clinical Trials as Topic; Cysteine; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Polyisoprenyl Phosphates; Protein Prenylation; Protein Processing, Post-Translational; ras Proteins; Sesquiterpenes

Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.

Topics: Alkyl and Aryl Transferases; Animals; Enzyme Inhibitors; Humans; Mice; Mutation; Neoplasms; Polyisoprenyl Phosphates; Protein Prenylation; Proto-Oncogene Proteins p21(ras); ras Proteins; Sesquiterpenes; Signal Transduction

To help characterize the FDFT1 gene and protein expression in cancer. Cholesterol represents an important structural component of lipid rafts. These specializations can be involved in pathways stimulating cell growth, survival and other processes active in cancer. This cellular compartment can be expanded by acquisition of cholesterol from the circulation or by its synthesis in a metabolic pathway regulated by the FDFT1 enzyme. Given the critical role this might play in carcinogenesis and in the behavior of cancers, we have examined the level of this enzyme in various types of human cancer. Our demonstration of elevated levels of FDFT1 mRNA and protein in some tumors relative to surrounding normal tissue identifies this as a possible biomarker for disease development and progression, and as a potential new target for the treatment of cancer.

Topics: Biomarkers, Tumor; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cholesterol; Disease Progression; DNA Methylation; Farnesyl-Diphosphate Farnesyltransferase; Genomics; Humans; Membrane Microdomains; Neoplasms; Polyisoprenyl Phosphates; Proteomics; RNA, Messenger; Sesquiterpenes; Tissue Array Analysis; Transcriptome

The statin family of drugs preferentially triggers tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for protein prenylation cannot explain increased statin sensitivity. Although ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the antiproliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity data indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anticancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.

Topics: Apoptosis; Biomarkers, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fluvastatin; Humans; Mevalonic Acid; Neoplasms; Polyisoprenyl Phosphates; Protein Prenylation; ras Proteins; Sesquiterpenes; Tumor Cells, Cultured; Zinc Finger E-box-Binding Homeobox 1

The schweinfurthins, a family of natural products derived from the isoprenoid biosynthetic pathway (IBP), have marked growth inhibitory activity. However, the biochemical basis for the schweinfurthins cellular effects has remained ill-defined. Here, the effects of the synthetic schweinfurthin, 3-deoxyschweinfurthin (3dSB) on multiple aspects of isoprenoid homeostasis are explored. Cytotoxicity assays demonstrate a synergistic interaction between 3dSB and the HMG-CoA reductase inhibitor lovastatin but not with other IBP inhibitors in a variety of human cancer cell lines. The cytotoxic effects of 3dSB were enhanced in cells incubated in lipid-depleted serum. 3dSB was found to enhance the lovastatin-induced decrease in protein prenylation. In addition, 3dSB decreases intracellular farnesyl pyrophosphate and geranylgeranyl pyrophosphate levels in both established cell lines and primary cells. To determine whether 3dSB alters the regulation of expression of genes involved in isoprenoid homeostasis, real-time PCR studies were performed in human cell lines cultured in either lipid-replete or -deplete conditions. These studies demonstrate that 3dSB abrogates lovastatin-induced upregulation of sterol regulatory element-containing genes and lovastatin-induced downregulation of ABCA1. In aggregate, these studies are the first to demonstrate that a schweinfurthin exerts pleiotropic effects on isoprenoid homeostasis.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Humans; Lovastatin; Neoplasms; Polyisoprenyl Phosphates; Prenylation; Sesquiterpenes; Stilbenes; Terpenes