scholarly journals Lipid-Producing Ciliochoroidal Melanoma with Expression of HMG-CoA Reductase

2020 ◽  
Vol 6 (6) ◽  
pp. 416-421
Author(s):  
David Van Ly ◽  
Duo Wang ◽  
Robert Max Conway ◽  
Michael Giblin ◽  
Sharron Liang ◽  
...  
Keyword(s):  
High Risk ◽  
Uveal Melanoma ◽  
Therapeutic Target ◽  
Mevalonate Pathway ◽  
Lipid Production ◽  
Published Data ◽  
Potential Therapeutic Target ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Uveal melanoma (UM) is the commonest primary intraocular malignancy in adults. There is limited published data on lipid production in UM. Here, we describe the clinical, histological, immunohistochemical, and molecular findings in a ciliochoroidal melanoma with lipid production and expression of the enzyme HMG-CoA reductase. This case highlights an unusual UM tumour phenotype with a high-risk molecular metastatic profile and discusses tumour lipogenesis and activation of the mevalonate pathway as a potential therapeutic target in managing lipidised ciliochoroidal UM.

Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3354-3362 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Marloes M. J. Kamphuis ◽  
Berris van Kessel ◽  
Henk M. Lokhorst ◽  
Andries C. Bloem
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Mevalonate Pathway ◽  
Cytochrome C Release ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Geranylgeranyl Transferase ◽  
Induced Apoptosis ◽  
Coa Reductase

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

Lovastatin as Salvage Immunomodulatory Therapy in Patients with Refractory and Relapsed Multipla Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1567-1567 ◽  
Author(s):  
Marek Hus ◽  
Norbert Grzasko ◽  
Dariusz Jawniak ◽  
Marta Szostek ◽  
Anna Dmoszynska
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Light Chain ◽  
Protein Level ◽  
Mevalonate Pathway ◽  
Sinus Bradycardia ◽  
Autologous Transplantation ◽  
M Protein ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Abstract In the recent years the treatment of patients with multiple myeloma (MM) has changed because of the introduction of new agents, mainly thalidomide (THAL) and its derivatives and bortezomib, an inhibitor of the 20S proteasome. Lovastatin (LOV) and other inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, have been demonstrated to exibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines including our own experiments. This observation induced us to administer LOV in combination with THAL and dexamethasone (DEX). We report here our preliminary experiences with THAL and LOV therapy in patients with refractory and relapsed MM. We have treated 81 patients with THAL+DEX regimen (TD) or THAL+DEX+LOV regimen (TLD). Patients received drugs orally in 28 day cycles. THAL was given from day 1 to day 28 each cycle and it was started at a initial dose of 100 mg daily increased to 300 mg daily. DEX was administered at a dose of 40 mg daily in days 1–4 each cycle. LOV was administered at a dose of 2 mg/kg in days 1–5 and 8–12 and at a dose of 0.5 mg/kg in days 15–28 each cycle. TLD regimen was administered to 43 patients and TD regimen to 38 patients. Patients characteristics before treatment were as follows: the median age 61.2 years; 61% of patients IgG, 26% IgA, 7% light chain and 6% other; 76% of patients were light chain kappa and 24% lambda; median serum M-protein level was 4.2 g/dl, bone marrow plasma cells 47%, hemoglobin 10.1 g/dl, platelets 197 G/l, beta-2-microglobulin 4.2 mg/ml, albumin 3.9 g/dl and LDH 292 IU. The median follow-up was 29 month. A clinical response, defined as a reduction of M-protein level by 50% or more, was observed in 67.8% of patients in TD group and in 88.0% in TLD group. CR i NCR was observed in 35.0% and 62.7% respectively. In 11 TLD (25.5%.) and 4 TD (10.5%) patients successful stem cell harvest was performed and mean amount of collected CD34+ cells was 8.2*106/kg. Successful autologous transplantation was performed in 8 patients from this group. Overall survival in TLD group (median 23.0 months) was significantly longer than in TD group (median 18.0 months). Similarly event free survival was longer in TLD (median 7.0 months) group than in TD group (4.5 months). We observed significant negative correlation between response and bone marrow infiltration (p=0.008), M-protein level (p=0.0004) and positive correlation between response and albumin level (p=0.005). Short time to reduction of M-protein by 50% was connected with better response. Common side effects as somnolence, fatigue and constipation were observed in about 45% of patients in TLD and TD groups. In 2 TLD and in 3 TD patients we diagnosed deep vein thrombosis. In 2 TLD patients sinus bradycardia was observed. Our results suggest that addition of LOV to THAL and DEX improves response rate in patients with refactory and relapsed MM. Moreover it is possible to harvest stem cells and perform autologous stem cells graft in patients treated with such regimen. A future prospective randomised study is needed to confirm the value of LOV or other HMG-CoA reductase inhibitors in the treatment of MM patients.

Modulation of YAP/ TAZ by statins to improve survival in epithelioid hemangioendothelioma (EHE).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23527-e23527
Author(s):  
Aparna Subramaniam ◽  
Jing Zheng ◽  
Sudha Yalamanchili ◽  
Anthony Paul Conley ◽  
Ravin Ratan ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Hippo Pathway ◽  
Nuclear Accumulation ◽  
Rank Test ◽  
Cancer Center ◽  
Hmg Coa Reductase ◽  
Number Of Patients ◽  
The Mean ◽  
Coa Reductase ◽  
Statin Use

e23527 Background: EHE is a rare soft tissue tumor of endothelial origin. It is distinguished by the pathognomonic WWTR1-CAMTA1 fusion (WWTR1 is the gene symbol for TAZ) seen in 90% of the tumors. YAP1-TFE3 fusion is less common and seen in 10% of the tumors. YAP and TAZ are critical downstream effectors of the Hippo pathway that regulate tumor development, progression, invasion and metastasis by modulating the expression of many Hippo pathway targets. Recent studies have shown that inhibition of HMG-CoA reductase, a key enzyme of the mevalonate pathway, can regulate YAP/ TAZ by preventing their nuclear accumulation and inhibiting their transcriptional activity. This has led to interest in the role of statins, which inhibit HMG-CoA reductase, as a modulator of YAP/ TAZ that could benefit patients with sarcoma, particularly EHE. Methods: A retrospective analysis was performed on patients with a diagnosis of EHE at M D Anderson Cancer Center. Patients were identified using the electronic database system and screened for statin use using EMRs. Demographic and clinical characteristics were tabulated. KM method was used to assess overall survival and log rank test was used to test survival differences between the statin use and non- statin use groups. All statistical analysis was performed using STATA 14. Results: 226 patients with EHE were identified. 27 of them had recorded statin use during the course of their disease. The median OS for the statin use group was not reached and the mean OS was 221 months. The median OS for the non- statin use group was 123.9 months, while the mean OS was 160 months. The difference in OS was not statistically significant between the two groups. The median follow-up time for our cohort was 36.6 months. Conclusions: Our findings indicate a trend towards improved survival for patients with EHE who have received statins over the course of their disease. Our study is limited by a small number of patients who received statins. Prospective studies are required to assess the therapeutic benefit of statins in EHE. [Table: see text]

scholarly journals Identification, Evolution, and Essentiality of the Mevalonate Pathway for Isopentenyl Diphosphate Biosynthesis in Gram-Positive Cocci

2000 ◽  
Vol 182 (15) ◽  
pp. 4319-4327 ◽  
Author(s):  
E. Imogen Wilding ◽  
James R. Brown ◽  
Alexander P. Bryant ◽  
Alison F. Chalker ◽  
David J. Holmes ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Genomic Analysis ◽  
Eukaryotic Cell ◽  
Infection Model ◽  
Isopentenyl Diphosphate ◽  
Gram Positive ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Gram Positive Cocci

ABSTRACT The mevalonate pathway and the glyceraldehyde 3-phosphate (GAP)–pyruvate pathway are alternative routes for the biosynthesis of the central isoprenoid precursor, isopentenyl diphosphate. Genomic analysis revealed that the staphylococci, streptococci, and enterococci possess genes predicted to encode all of the enzymes of the mevalonate pathway and not the GAP-pyruvate pathway, unlike Bacillus subtilis and most gram-negative bacteria studied, which possess only components of the latter pathway. Phylogenetic and comparative genome analyses suggest that the genes for mevalonate biosynthesis in gram-positive cocci, which are highly divergent from those of mammals, were horizontally transferred from a primitive eukaryotic cell. Enterococci uniquely encode a bifunctional protein predicted to possess both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and acetyl-CoA acetyltransferase activities. Genetic disruption experiments have shown that five genes encoding proteins involved in this pathway (HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase) are essential for the in vitro growth of Streptococcus pneumoniae under standard conditions. Allelic replacement of the HMG-CoA synthase gene rendered the organism auxotrophic for mevalonate and severely attenuated in a murine respiratory tract infection model. The mevalonate pathway thus represents a potential antibacterial target in the low-G+C gram-positive cocci.

HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort

Oncogene ◽  
2021 ◽  
Author(s):  
Elyse C. Page ◽  
Susan L. Heatley ◽  
Laura N. Eadie ◽  
Barbara J. McClure ◽  
Charles E. de Bock ◽  
...  
Keyword(s):  
Down Syndrome ◽  
High Risk ◽  
Significant Role ◽  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
High Risk Cohort

scholarly journals Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase

2020 ◽  
Vol 61 (12) ◽  
pp. 1675-1686
Author(s):  
Marco De Giorgi ◽  
Kelsey E. Jarrett ◽  
Jason C. Burton ◽  
Alexandria M. Doerfler ◽  
Ayrea Hurley ◽  
...  
Keyword(s):  
Er Stress ◽  
Mevalonate Pathway ◽  
Critical Role ◽  
Cellular Level ◽  
Hmg Coa Reductase ◽  
Biochemical Level ◽  
Genetic Deletion ◽  
Coa Reductase ◽  
Rate Limiting ◽  
Specific Deletion

HMG-CoA reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing nonsterol isoprenoids, such as dolichol, ubiquinone, and farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on nonsterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the nonsterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr-null hepatocytes showed ER stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds-null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

scholarly journals Enterococcus faecalis Acetoacetyl-Coenzyme A Thiolase/3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase, a Dual-Function Protein of Isopentenyl Diphosphate Biosynthesis

2002 ◽  
Vol 184 (8) ◽  
pp. 2116-2122 ◽  
Author(s):  
Matija Hedl ◽  
Autumn Sutherlin ◽  
E. Imogen Wilding ◽  
Marie Mazzulla ◽  
Damien McDevitt ◽  
...  
Keyword(s):  
Gene Product ◽  
Enterococcus Faecalis ◽  
Active Site ◽  
Coenzyme A ◽  
Mevalonate Pathway ◽  
Dual Function ◽  
Isopentenyl Diphosphate ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Active Site Histidine

ABSTRACT Many bacteria employ the nonmevalonate pathway for synthesis of isopentenyl diphosphate, the monomer unit for isoprenoid biosynthesis. However, gram-positive cocci exclusively use the mevalonate pathway, which is essential for their growth (E. I. Wilding et al., J. Bacteriol. 182:4319-4327, 2000). Enzymes of the mevalonate pathway are thus potential targets for drug intervention. Uniquely, the enterococci possess a single open reading frame, mvaE, that appears to encode two enzymes of the mevalonate pathway, acetoacetyl-coenzyme A thiolase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Western blotting revealed that the mvaE gene product is a single polypeptide in Enterococcus faecalis, Enterococcus faecium, and Enterococcus hirae. The mvaE gene was cloned from E. faecalis and was expressed with an N-terminal His tag in Escherichia coli. The gene product was then purified by nickel affinity chromatography. As predicted, the 86.5-kDa mvaE gene product catalyzed both the acetoacetyl-CoA thiolase and HMG-CoA reductase reactions. Temperature optima, ΔHa and Km values, and pH optima were determined for both activities. Kinetic studies of acetoacetyl-CoA thiolase implicated a ping-pong mechanism. CoA acted as an inhibitor competitive with acetyl-CoA. A millimolar Ki for a statin drug confirmed that E. faecalis HMG-CoA reductase is a class II enzyme. The oxidoreductant was NADP(H). A role for an active-site histidine during the first redox step of the HMG-CoA, reductase reaction was suggested by the ability of diethylpyrocarbonate to block formation of mevalonate from HMG-CoA, but not from mevaldehyde. Sequence comparisons with other HMG-CoA reductases suggest that the essential active-site histidine is His756. The mvaE gene product represents the first example of an HMG-CoA reductase fused to another enzyme.

scholarly journals Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation

2001 ◽  
Vol 1 (3) ◽  
pp. 108-113 ◽  
Author(s):  
Naima Gueddari-Pouzols ◽  
Patrick Duriez ◽  
Christine Chomienne ◽  
Aurélie Trussardi ◽  
Jean Claude Jardillier
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Mevalonate Pathway ◽  
Competitive Inhibitor ◽  
Farnesyltransferase Inhibitors ◽  
Differentiation Process ◽  
Induced Differentiation ◽  
Hmg Coa Reductase ◽  
Potent Inducer ◽  
Coa Reductase

Alltransretinoic acid (ATRA) is a potent inducer of differentiation of HL-60 cell line. The pretreatment of the cells by compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the ATRA-induced cell differentiation. At 50 nM, the percentage of cell differentiation is 34.9% ± 2 and 73% ± 2.96 in the control and compactin-treated cells, respectively. The removal of compactin boosts the level of HMG-CoA reductase and therefore the biosynthesis of sterol and nonsterol isoprenoid compounds. The participation of sterol and nonsterol pathway was then investigated. The supply of an excess of cholesterol (up to 80 μg/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% ±0.1 to 54% ±2.8. A concomitant decrease of cell growth (51% ± 6.4) was observed. The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298) has no effect on the cell differentiation process. By contrast, the farnesyltransferase inhibitors (FTI-II and FTI-277) completely abolish theATRA-induced differentiation, thus confirming the involvement of farnesylated proteins in the differentiation mechanism.

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