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PubMed2004

Mutual amplification of apoptosis by statin-induced mitochondrial stress and doxorubicin toxicity in human rhabdomyosarcoma cells.

Besides their cholesterol-lowering effect, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) show antiproliferative behaviour, which has been suggested as a promising anticancer strategy. However, the signalling cascades leading to statin-induced death of cancer cells are poorly characterized. Here we show that statins activate the mitochondrial pathway of apoptosis in rhabdomyosarcoma RD cells via translocation of Bax from the cytosol to mitochondria. The prototypical representative of statins, simvastatin, induced consecutive activation of caspase 9 and 3 in a concentration-dependent manner. The permeability transition pore inhibitor bongkrekic acid was capable of completely preventing simvastatin-induced caspase 9 and 3 activity, corroborating the mitochondrial pathway of apoptosis as the sole mechanism of statin action. Alternative pathways via death receptors, that is, caspase 8 or calpain activation, were not triggered by simvastatin. Simvastatin-treated RD cells could be completely rescued from apoptosis by the co-application of mevalonic acid, indicating that deprivation of cholesterol precursors is essential for statin-induced apoptosis. However, pretreatment with subthreshold concentrations of simvastatin was sufficient to augment doxorubicin toxicity via the mitochondrial apoptotic machinery. Moreover, the presence of doxorubicin increased the potency of simvastatin to trigger caspase activation. Taken together, these data highlight the therapeutic anticancer potential of statins and their additivity and mutual sensitization, in combination with doxorubicin in human rhabdomyosarcoma cells.

Apoptosis↗
PubMed1983

Biosynthesis of abscissic acid.

The fungus Cercospora rosicola has been studied as a model system for abscissic acid biosynthesis. 1'-dDeoxyabscissic acid and 4'-hydroxy-a-ionylidene acetic acid have been identified as endogenous compounds in this fungus. The results of feeding these and other putative intermediates suggest that abscissic acid biosynthesis proceeds via the successive oxidations of a 3-methyl-5-(2',6',6'-trimethylcyclohex-2'-en-1'-yl)-2,4-pentadienyl intermediate. Preliminary results suggest that a similar pathway may operate in plants.

Abscisic Acid↗
PubMed2003

Monoterpene regulation of Ras and Ras-related protein expression.

Monoterpenes, derived primarily from plants, are products of the isoprenoid biosynthetic pathway and function as chemical messengers with diverse functions. The biochemical bases for these activities are largely undefined. The Ras small GTPase superfamily of proteins consists of isoprenylated proteins that play key roles in signal transduction pathways known to regulate diverse cellular functions. In these studies, we have examined the effects of the monoterpenes on expression of Ras and Ras-related proteins, in the absence and presence of mevalonate depletion. Although prior studies have suggested that monoterpenes inhibit isoprenyl transferases, our studies clearly show that select monoterpenes inhibit up-regulation of Ras and the Ras-related proteins. A structure-activity relationship model for these effects was defined. The ability of monoterpenes to regulate the expression of the Ras-related proteins was found to be independent of effects on cell proliferation or total cellular protein synthesis/degradation. This regulatory function of monoterpenes suggests a role for these plant-derived compounds in altering signal transduction elements.

Cell Division↗
PubMed1989

Modification of nuclear lamin proteins by a mevalonic acid derivative occurs in reticulocyte lysates and requires the cysteine residue of the C-terminal CXXM motif.

The C-terminus of nuclear lamins (CXXM) resembles a C-terminal motif (the CAAX box) of fungal mating factors and ras-related proteins. The CAAX box is subject to different types of post-translational modifications, including proteolytic processing, isoprenylation and carboxyl methylation. By peptide mapping we show that both chicken lamins A and B2 are processed proteolytically in vivo. However, whereas the entire CXXM motif is cleaved from lamin A, at most three C-terminal amino acids are removed from lamin B2. Following translation of cDNA-derived RNAs in reticulocyte lysates, lamin proteins specifically incorporate a derivative of [14C]mevalonic acid (MV), i.e. the precursor of a putative isoprenoid modification. Remarkably, no MV is incorporated into lamin B2 translated from a mutant cDNA encoding alanine instead of cysteine in the C-terminal CXXM motif. These results implicate this particular cysteine residue as the target for modification of lamin proteins by an isoprenoid MV derivative, and they indicate that isoprenylation is amenable to studies in cell-free systems. Moreover, our observations suggest that C-terminal processing of newly synthesized nuclear lamins is a multi-step process highly reminiscent of the pathway elaborated recently for ras-related proteins.

Animals↗
PubMed1976

Enzymatic synthesis of C40 carotenes by cell-free preparation from Halobacterium cutirubrum.

[14C]Mevalonate or (14C)isopentenyl pyrophosphate was found to be converted to transphytoene, trans-phytofluene, lycopene, and beta-carotene by a cell-free 270 000 X g supernatant fraction prepared from Halobacterium cutirubrum cells that were broken by manual grinding with glass beads. Incubations were done under N2 in the dark at 37 degrees C in 4 M NaCl in presence of FAD, NADP, and MgCl2; ATP was also added when mevalonate was the substrate. This system was also capable of converting trans-(14C)phytoene to beta-carotene via the intermediates trans-phytofluene, zeta-carotene, neurosporene, lycopene, and gamma-carotene. Each of these labelled intermediates on incubation separately with the same enzyme system was shown to be converted to the intermediates farther down the pathway. The results of this study show that the biosynthetic pathway for the formation of C40 carotenes in H. cutirubrum proceeds as follows: isopentenyl pyrophosphate leads to trans-phytoene leads to trans-phytofluene leads to zeta-carotene leads to neurosporene leads to lycopene leads to gamma-carotene leads to beta-carotene. This pathway differs from that in higher plants in that the cis isomers of phytoene and phytofluene are not on the main pathway of carotene biosynthesis, as they are in higher plants. Furthermore, trans-phytoene, which has not been reported to have any role in higher plants, appears to be the main intermediate in carotene biosynthesis in H. cutirubrum.

Carotenoids↗
PubMed1994

Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle.

Lactate and pyruvate cross cell membranes via a monocarboxylate transporter (MCT) with well-defined properties but undefined molecular structure. We report the cloning of a cDNA encoding MCT1, a monocarboxylate transporter whose properties resemble those of the erythrocyte MCT, including proton symport, trans acceleration, and sensitivity to alpha-cyanocinnammates. A Phe to Cys substitution in MCT1 converts it to Mev, a mevalonate transporter. MCT1 is abundant in erythrocytes, cardiac muscle, and basolateral intestinal epithelium. In skeletal muscle it is restricted to mitochondria-rich myocytes. As sperm traverse the epididymis, MCT1 switches from sperm to epithelial cells. MCT1 is present at low levels in liver, suggesting another MCT in this tissue. By exporting lactate from intestine and erythrocytes, MCT1 participates in the Cori cycle. It also participates in novel pathways of monocarboxylate metabolism in muscle and sperm.

Animals↗
PubMed1997

Isoprenoid metabolism in the vertebrate retina.

Herein, studies concerning the biosynthesis, intracellular transport and utilization of isoprenoid lipids in vertebrate retinas are reviewed, with particular regard to rod photoreceptor cells and the assembly of rod outer segment (ROS) disk membranes. Initial in vitro studies with bovine retinas showed that [3H]mevalonate is metabolized primarily to squalene and 'methylated' sterols, rather than to cholesterol. Subsequently, similar results were obtained with frog retinas using [3H]acetate as a precursor, and the absolute rate of the sterol pathway was determined in vitro with 3H2O. With the aid of vesicular transport inhibitors, energy poisons, and reduced temperature, it was demonstrated that lipid and protein trafficking mechanisms in the rod cell are separate and independent from one another. In vivo, the majority of newly synthesized squalene in the frog retina is not metabolized to sterols; rather, it is transported to the ROS, where it turns over in parallel with the disk membranes. The remaining squalene is converted slowly to cholesterol, much of which becomes incorporated into the ROS. In contrast, the in vivo metabolism of [3H]acetate to cholesterol in the rat retina is relatively efficient and rapid. However, in both frog and rat, retinal cholesterol turnover is slow (> 60 days), suggesting the existence of a retention mechanism that minimizes the need for de novo biosynthesis. The use of pharmacological approaches to assess the biological roles of isoprenoid lipids and protein prenylation in the retina and the mechanism of retinal cholesterol homeostasis are discussed.

Animals↗
PubMed2005

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses.

Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, a fulminant microglial-mediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the Abeta-stimulated expression of interleukin-1beta and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal Abeta production and microglia-directed inflammation.

Amyloid beta-Peptides↗
PubMed1977

Ertosterol biosynthesis in Saccharomyces cerevisiae: mutants deficient in the early steps of the pathway.

Thermosensitive mutants, auxotrophic for ergosterol synthesis, have been isolated, analyzed genetically and their enzymatic deficiencies investigated. These mutants were classified into seven unlinked complementation groups. These groupes lack the following enzymatic activities: squalene epoxidase (erg 1), 2,3-oxidosqualene-lanosterol cyclase (erg 7), phosphomevalonic kinase (erg 8), mevalonic kinase (erg12) and squalene synthetase (erg 9, erg 10, erg 11).

Epoxy Compounds↗
PubMed1987

Human bronchial epithelial cells synthesize cholesterol sulfate during squamous differentiation in vitro.

Epithelial cells of the airways can, under pathological conditions, undergo squamous metaplasia. The accumulation of cholesterol sulfate has recently been described as a new marker for squamous cell differentiation in rabbit tracheal epithelial cells. We now report that normal human bronchial epithelial cells in culture metabolically incorporated [35S]-sulfate and [3H]-mevalonate into material indistinguishable from cholesterol sulfate by the criteria of solubility in organic solvents, behavior on ion-exchange chromatography, susceptibility to solvolysis, and behavior on thin-layer chromatography before and after solvolysis. The accumulation of cholesterol [35S]-sulfate correlated well with squamous cell differentiation (as measured by cross-linked envelope formation), which occurred when the cells reached confluency. The increase in the level of cholesterol sulfate could be inhibited by the inclusion of retinoic acid in the cell-culture medium. The addition of phorbol-12-myristate-13-acetate or the presence of high Ca2+ concentration in the medium stimulated the accumulation of cholesterol sulfate. An increased activity of cholesterol sulfotransferase seems to account for the cholesterol sulfate accumulation. The original observation of cholesterol sulfate accumulation during squamous differentiation thus extends across species lines and strengthens the suggestion that the cholesterol sulfate may play an important role in this type of differentiation. Moreover, cholesterol sulfate provides a sensitive biochemical marker to study this pathway of differentiation of human bronchial epithelial cells.

Bronchi↗
PubMed2006

RhoA-mediated, tumor necrosis factor alpha-induced activation of NF-kappaB in rheumatoid synoviocytes: inhibitory effect of simvastatin.

OBJECTIVE: Increasing evidence indicates that RhoA may play a central role in the inflammatory response. This study was conducted to examine the role of RhoA in mediating the activation of NF-kappaB in tumor necrosis factor alpha (TNFalpha)-stimulated rheumatoid synoviocytes, and to evaluate the modulatory effects of statins on the TNFalpha-induced activation of RhoA and NF-kappaB and the secretion of proinflammatory cytokines by rheumatoid synoviocytes. METHODS: Rheumatoid synoviocytes obtained from patients with active rheumatoid arthritis were stimulated with TNFalpha and incubated with simvastatin (SMV) (1 muM). RhoA activity was assessed by a pull-down assay. NF-kappaB DNA binding activity and nuclear translocation of NF-kappaB were measured by a sensitive multiwell colorimetric assay and confocal fluorescence microscopy, respectively. RESULTS: TNFalpha stimulation elicited a robust increase in RhoA activity in a dose-dependent manner, and SMV mitigated this increase. TNFalpha also hastened NF-kappaB nuclear translocation of subunit p65 and increased DNA binding activity, luciferase reporter gene expression, degradation of IkappaB, and secretion of interleukin-1beta (IL-1beta) and IL-6. SMV prevented the increase in NF-kappaB activation and rise in IL-1beta and IL-6 levels induced by TNFalpha, whereas mevalonate and geranylgeranyl pyrophosphate reversed the inhibitory effects of SMV on activation of NF-kappaB and RhoA. Furthermore, cotransfection with a dominant-negative mutant of RhoA demonstrated that the TNFalpha-induced signaling pathway involved sequential activation of RhoA, leading to NF-kappaB activation and, ultimately, to secretion of cytokines. CONCLUSION: This study identifies RhoA as the key regulator of TNFalpha-induced NF-kappaB activation, which ultimately results in the secretion of proinflammatory cytokines in rheumatoid synoviocytes. The findings provide a new rationale for the antiinflammatory effects of statins in inflammatory arthritis.

Aged↗
PubMed1967

Nature, intracellular distribution and formation of terpenoid quinones in Euglena gracilis.

1. Light-grown cells of Euglena gracilis strain Z, var. bacillaris and 1224/5g contain phylloquinone, plastoquinone, alpha-tocopherol, alpha-tocopherolquinone and ubiquinone-9 (i.e. ubiquinone with 9 isoprene units/mol.). 2. The concentration (per g. dry wt.) of plastoquinone (and chlorophyll) in light-grown cells of strain Z was governed by the composition of the culture medium and age of the cells. Highest yields of plastoquinone were obtained under autotrophic conditions, the concentration reaching a maximum after 6-8 days' growth. The concentrations were less in heterotrophic media. The concentration of ubiquinone was relatively unaffected by the age of the cells or composition of the medium. 3. In light-grown cells of strain Z plastoquinone, alpha-tocopherolquinone and alpha-tocopherol were mainly localized in the chloroplast; ubiquinone was found to be in the mitochondria. 4. Etiolated (dark-grown) cells of strain Z contained no phylloquinone, plastoquinone or alpha-tocopherolquinone; alpha-tocopherol was present in lower concentrations compared with light-grown cells; ubiquinone concentrations were similar to those for light-grown cells. The presence of alpha-tocopherol in etiolated cells suggested that this chromanol was not entirely confined to the chloroplast. 5. On illumination of etiolated cells of strain Z the chloroplastidic components plastoquinone, alpha-tocopherolquinone and alpha-tocopherol were synthesized in step with chloroplast formation. Ubiquinone concentrations, as expected, were unaffected. 6. [2-(14)C]Mevalonic acid, the specific distal terpenoid precursor, was not incorporated into any of the terpenoid components examined. This was attributed to the impermeability of the cell wall to this compound, rather than to a novel pathway of terpenoid biosynthesis.

Bacteriological Techniques↗
PubMed2005

Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway.

OBJECTIVE: Pulsatile forces regulate vascular remodeling and trigger vascular diseases such as saphenous vein graft disease. The saphenous vein is exposed to high pressure and pulsatility only after implantation. Statins have been proved to reduce the incidence of vein graft failure. Thus, we investigated the molecular mechanisms of pulsatile stretch-induced saphenous vein smooth muscle cell (SMC) proliferation and potential beneficial effects of statins. METHODS AND RESULTS: Human saphenous vein SMCs were subjected to cyclic stretch (60 cycles/min) in Flex I plates. Cerivastatin and simvastatin significantly prevented stretch-induced increase in SMC proliferation. Stretch induced the membrane accumulation of Rho A and Rho kinase inhibitors (Y-27632 and hydroxyfasudil) and dominant negative Rho A mutant significantly prevented stretch-induced SMC proliferation. In addition, stretch increased the levels of both p44/42 mitogen-activated protein (MAP) kinase and Akt phosphorylation. MAP kinase kinase (MEK)1/2 inhibitor U0126, phosphatidylinositol (PI) 3-kinase inhibitors (wortmannin and LY294002), and dominant negative Akt mutant significantly prevented stretch-induced SMC proliferation. Cerivastatin significantly prevented stretch-induced membrane accumulation of Rho A. On the other hand, stretch-induced phosphorylation of p44/42 MAP kinase and Akt was not prevented by cerivastatin. Mevalonate restored the preventive effect of cerivasatain on stretch-induced Rho A membrane accumulation. Stretch induced hyperphosphorylation of retinoblastoma protein (pRb), which was prevented by cerivastatin and the Rho kinase inhibitors. CONCLUSION: Statins prevent stretch-induced saphenous vein SMC proliferation via inhibition of the Rho/Rho-kinase pathway. This may explain the beneficial effects of this class of drug, especially for patients after coronary artery bypass grafting.

Blotting, Western↗
PubMed1976

Actinomycin D-induced enhancement of ubiquinone biosynthesis in rat.

Administration of actinomycin D to fasted rats induces an enhancement of the labeling of hepatic ubiquinone by [2-14C] acetate both in vivo and in vitro. The incorporation of [2-14C] mevalonate into ubiquinone is also increased, although to a significantly lesser extent; this, however, presumably results from greater uptake of the labeled precursor by liver of drug-treated rats. The drug-administered animals show increased activity of liver microsomal mevalonate: NADP oxidoreductase, the rate-limiting enzyme in isoprenoid biogenesis. The incorporation of [u-14C] benzoic acid and CH3-[14C] methionine into ubiquinone in liver slices, however, reveals a decrease in actinomycin D administered rats. This appears to be due to a specific inhibition of the pathway leading to the benzoquinone moiety of ubiquinone and not to an increase in the pool-size of the precursors. The stimulatory effect of the drug on ubiquinone biosynthesis is also observable in cholesterol-fed rats. The actinomycin D-induced increase in ubiquinone biosynthesis is dependent on new protein synthesis since the effect is abolished by treating the animals with either cycloheximide or puromycin.

Alcohol Oxidoreductases↗
PubMed2003

Beyond lipid-lowering: effects of statins on endothelial nitric oxide.

Endothelial dysfunction is now recognised as an important process in the pathogenesis of atherosclerosis. Nitric oxide (NO) release by the endothelium regulates blood flow, inflammation and platelet aggregation, and consequently its disruption during endothelial dysfunction can decrease plaque stability and encourage the formation of atherosclerotic lesions and thrombi. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) are often utilised in the prevention of coronary heart disease due to their efficacy at lowering lipid levels. However, statins may also prevent atherosclerotic disease by non-lipid or pleiotropic effects, for example, improving endothelial function by promoting the production of NO. There are various mechanisms whereby statins may alter NO release, such as inhibiting the production of mevalonate and important isoprenoid intermediates, thereby preventing the isoprenylation of the small GTPase Rho, which negatively regulates the expression of endothelial nitric oxide synthase (eNOS). Furthermore, statins may also increase eNOS activity via post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3 K/Akt) pathway and/or through an interaction with the molecular chaperone heat-shock protein 90 (HSP90). Data suggest that statins may vary in their efficacy for enhancing the release of NO, and the mechanisms dictating these differences are not yet clear. By increasing NO production, statins may interfere with atherosclerotic lesion development, stabilise plaque, inhibit platelet aggregation, improve blood flow and protect against ischaemia. Therefore, the ability of statins to improve endothelial function through the release of NO may partially account for their beneficial effects at reducing the incidence of cardiovascular events.

Arteriosclerosis↗
PubMed1990

Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2.

The activation of human natural killer (NK) cell cytotoxicity by interleukin 2 (IL-2) is well established, although the biochemical mechanisms of this stimulation have not yet been fully delineated. Earlier, we reported that treatment of NK cells with an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase such as compactin or lovastatin significantly abrogates the in vitro killing of a susceptible human erythroleukemic cell line and that this inhibition can be completely reversed by 2 hr of exposure to mevalonate (J. Cell. Physiology 139:550-557, 1989). We report here that 24 hr of treatment with IL-2 also reverses lovastatin inhibition of NK cell function. In addition to natural cytotoxicity, IL-2 also restores chemotactic and antibody dependent cellular cytotoxicity functions to lovastatin-treated cells. IL-2 does not stimulate proliferation of these cells during this time period, nor does it affect the phenotypic composition of the NK cell preparations. Although IL-2 was able to reverse the lovastatin-mediated inhibition of every cell function we examined, it had no effect on the inhibition of cholesterol biosynthesis as measured by [3H]acetate incorporation into non-saponifiable lipids, nor did it stimulate HMG CoA reductase activity. These findings support the hypothesis that there is a non-sterol isoprenoid product which is required for NK cell cytotoxicity and chemotaxis. In addition, the data suggest that IL-2 stimulation of NK cells proceeds by an isoprenoid-independent pathway.

Acetates↗
PubMed2005

HMGCoA reductase potentiates hedgehog signaling in Drosophila melanogaster.

Drosophila HMGCoA reductase (hmgcr) catalyzes the biosynthesis of a mevalonate precursor for isoprenoids and has been implicated in the production of a signal by the somatic gonadal precursor cells (SGPs) that attracts migrating germ cells. Here, we show that hmgcr functions in the hedgehog (hh) signaling pathway. When hmgcr activity is reduced, high levels of Hh accumulate in hh-expressing cells in each parasegment, while the adjacent "Hh-receiving" cells cannot sustain wg expression and fail to relocalize the Smoothened (Smo) receptor. Conversely, ectopic Hmgcr upregulates Hh signaling when it is produced in hh-expressing cells, but has no effect when produced in the receiving cells. These findings suggest that Hmgcr might orchestrate germ cell migration by promoting the release and/or transport of Hh from the SGPs. Consistent with this model, there are substantial germ cell migration defects in trans combinations between hmgcr and mutations in different components of the hh pathway.

Animals↗