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Lovastatin effect on breast tumors in HER2/neu transgenic mice

ABSTRACT: The statins are a family of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, which converts acetyl-CoA into mevalonic acid. Since HMG-CoA reductase catalyzes the rate-limiting step in the mevalonate pathway of cholesterol biosynthesis, it was thought that the major clinical benefit of statins was to reduce cholesterol levels in the bloodstream; statins are thus in wide clinical use for the prevention and treatment of cardiovascular disease. Nonetheless, mevalonate is also the precursor of isoprenoid compounds, which are substrates for the post-translational modification of many proteins involved in cell signaling. The blockade of isoprenoid synthesis might explain the pleiotropic effects described for statins in extrahepatic tissues, including inhibition of pathogen infection and anti-inflammatory and immunomodulatory activities. We used microarrays to find differentially expressed genes in spontaneous breast tumors from mice treated with lovastatin (Lov) or vehicle (ethanol) as control.

ORGANISM(S): Mus musculus

PROVIDER: GSE42787 | GEO | 2015/05/19

SECONDARY ACCESSION(S): PRJNA183135

REPOSITORIES: GEO

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Lovastatin effect on breast tumors in HER2/neu transgenic mice

Project description:The statins are a family of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, which converts acetyl-CoA into mevalonic acid. Since HMG-CoA reductase catalyzes the rate-limiting step in the mevalonate pathway of cholesterol biosynthesis, it was thought that the major clinical benefit of statins was to reduce cholesterol levels in the bloodstream; statins are thus in wide clinical use for the prevention and treatment of cardiovascular disease. Nonetheless, mevalonate is also the precursor of isoprenoid compounds, which are substrates for the post-translational modification of many proteins involved in cell signaling. The blockade of isoprenoid synthesis might explain the pleiotropic effects described for statins in extrahepatic tissues, including inhibition of pathogen infection and anti-inflammatory and immunomodulatory activities. We used microarrays to find differentially expressed genes in spontaneous breast tumors from mice treated with lovastatin (Lov) or vehicle (ethanol) as control. Standard single channel experimental design with biological replicates: gene expression signals from 5 treated tumor samples were compared to 5 non-treated tumor samples using Affymetrix GeneChips (MG430 v2.0).

2015-05-19 | E-GEOD-42787 | biostudies-arrayexpress

Role of mevalonate pathway intermediates in anticancer effect of statins

Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.

2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress

Transcriptomic profiling of differentially expressed mRNA, lncRNA and circRNA in atorvastatin-treated human endothelial cells

Project description:Statins are competitive inhibitors of (3-hydroxy-3-methylglutaryl coenzyme A) HMG-CoA reductase. The primary mechanism of statins is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis. Statins exert pleiotropic vasoprotective and atheroprotective effects in the vasculature, with its mechanism of action being incompletely understood.To depict the statin-regulated mRNA,long non-coding RNA (lncRNA) and circular RNA (circRNA) in human endothelial cells, we performed transcriptomic profiling of human umbilical vein endothelial cells (HUVECs) with atorvastatin treatment.Differentially expressed mRNA, lncRNA and circRNA may represent novel therapeutic targets against cardiovascular diseases.

2023-05-31 | GSE176531 | GEO

Suppression of statin effectiveness by copper and zinc in yeast and human cells

Project description:Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans.

2010-10-29 | GSE25004 | GEO

Lovastatin Promotes the Self-renewal of Murine and Primate Spermatogonial Stem Cells

Project description:The spermatogonial stem cells (SSCs) niche is critical for SSC maintenance and the subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby result in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse spermatogonial stem cells (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Likewise, other statins exhibit similar effects on SSC self-renewal. Remarkably, the treatment by Lovastatin could promote the self-renewal of mSSCs in the male gonadotoxicity model generated by busulfan injection. Noteworthy, we demonstrate that Lovastatin could significantly enhance the self-renewal of in vitro cultured primate SSCs. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain male infertility using small compounds.

2022-06-10 | GSE182897 | GEO

Suppression of statin effectiveness by copper and zinc in yeast and human cells

2010-10-29 | E-GEOD-25004 | biostudies-arrayexpress

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

Project description:Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone-marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on-target, via inhibition of HMG-CoA reductase. These results suggest that statins should be re-evaluated as anti-leukemia agents, and illustrate the power of merging physiologically-relevant models with high-throughput screening.

2013-09-20 | GSE51033 | GEO

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

2013-09-20 | E-GEOD-51033 | biostudies-arrayexpress

25-Hydroxycholesterol inhibits hantavirus infection through reprogramming cholesterol metabolism and suggest statins as candidate hantavirus inhibitors

Project description:Hantavirus causes two kinds of acute diseases; hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), and it is still a major health concern due to high mortality and lack of effective treatment. Interferon is only effective to inhibit hantavirus infection at a very early stage. Several interferon-stimulated genes (ISGs) have been indicated to inhibit hantavirus infection. The cholesterol 25-hydroxylase (CH25H) has been indicated as an ISG, which encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25HC). 25HC plays an important role in regulating cholesterol biosynthesis and inhibits multiple enveloped virus infections. Here, we showed that Hantaan virus (HTNV), the prototype hantavirus, induces CH25H in infected cells. Overexpression of CH25H and treatment of its enzymatic product 25HC both inhibit HTNV infection, possibly through lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase regulation (HMG-CoA reductase, HMGCR) that inhibit cholesterol synthesis. Additionally, cholesterol lowering drugs, HMGCR-targeting statins process potent hantavirus inhibition effects. Taken together, our results indicate that the 25HC and statins were potential antivirals against hantavirus infection.

2024-06-27 | GSE252127 | GEO

Claudin-7 in keratinocytes is downregulated by the inhibition of HMG-CoA reductase and is highly expressed in the stratum granulosum of the psoriatic epidermis

Project description:Background: Cholesterol is de novo synthesized in the upper epidermis and plays an important role in maintaining the normality of skin. Studying the impact of the inhibition of cholesterol de novo synthesis in the epidermis may help understand how skin homeostasis is regulated. Objective: In this study, we created a gene expression profile to investigate the effect of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on epidermal homeostasis. Methods: A microarray analysis was performed using normal keratinocytes with or without HMG-CoA reductase inhibitor (pitavastatin) treatment. Real-time PCR confirmed the reproducibility of genes with altered expression in keratinocytes treated with HMG-CoA reductase inhibitors. Among these genes, we focused on reduced expression of claudin 7 histologically confirmed by immunohistochemical staining, in situ hybridization, and immunoelectron microscopy. Results: Claudin-7 was highly expressed in the stratum granulosum of psoriatic lesions but was not expressed in the normal epidermis. Immunoelectron microscopy revealed that claudin-7 was localized in the keratohyalin granules of psoriatic lesions. Conclusion: These results indicate that claudin-7 expression was regulated by HMG-CoA reductase in the epidermis and might play a pathogenic role in the keratohyalin granules found in the epidermal granular layer of psoriasis.

2021-07-20 | GSE180418 | GEO

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