Different statins produce highly divergent changes in gene expression profiles of human hepatoma cells: a pilot study.

Leszczynska, Agata; Góra, Monika; Płochocka, Danuta; Hoser, Grażyna; Szkopińska, Anna; Koblowska, Marta; Iwanicka-Nowicka, Roksana; Kotliński, Maciej; Rawa, Katarzyna; Kiliszek, Marek; Burzyńska, Beata

doi:10.18388/abp.2011_2235

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…Similar results were observed in human skeletal muscle-like cells [14] and human hepatoma HepG2 cells [15]. In those studies statins increased the expression of numerous cholesterol synthesis-related genes.…”

Section: Discussionsupporting

confidence: 80%

The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

et al. 2013

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BackgroundThe yeast Saccharomyces cerevisiae can be a useful model for studying cellular mechanisms related to sterol synthesis in humans due to the high similarity of the mevalonate pathway between these organisms. This metabolic pathway plays a key role in multiple cellular processes by synthesizing sterol and nonsterol isoprenoids. Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the cholesterol synthesis pathway. However, the effects of statins extend beyond their cholesterol-lowering action, since inhibition of HMGR decreases the synthesis of all products downstream in the mevalonate pathway. Using transgenic yeast expressing human HMGR or either yeast HMGR isoenzyme we studied the effects of simvastatin, atorvastatin, fluvastatin and rosuvastatin on the cell metabolism.ResultsStatins decreased sterol pools, prominently reducing sterol precursors content while only moderately lowering ergosterol level. Expression of genes encoding enzymes involved in sterol biosynthesis was induced, while genes from nonsterol isoprenoid pathways, such as coenzyme Q and dolichol biosynthesis or protein prenylation, were diversely affected by statin treatment. Statins increased the level of human HMGR protein substantially and only slightly affected the levels of Rer2 and Coq3 proteins involved in non-sterol isoprenoid biosynthesis.ConclusionStatins influence the sterol pool, gene expression and protein levels of enzymes from the sterol and nonsterol isoprenoid biosynthesis branches and this effect depends on the type of statin administered. Our model system is a cheap and convenient tool for characterizing individual statins or screening for novel ones, and could also be helpful in individualized selection of the most efficient HMGR inhibitors leading to the best response and minimizing serious side effects.

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Section: Discussionsupporting

confidence: 80%

The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

et al. 2013

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“…( Figure 2B and C). On mRNA level as assessed by qPCR, we found that statins increased HMGCS and HMGCR ( Figure 2D), the same effects that have been described for liver including LDL receptor 23 . Eight protein coding transcript variants are known for LDLR.…”

Section: Muscle Cells Possess a Similar Repertoire For Cholesterol Bisupporting

confidence: 82%

A prostaglandin alpha F2 analog protects from statin-induced myopathic changes in primary human muscle cells

Popp

Haafke

et al. 2018

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Statins reduce plasma cholesterol levels and are effective in secondary cardiovascular disease prevention. However, statin related muscle side effects are a constant problem for patients and doctors because compliance in taking them is severely influenced by the side effects. The mechanism of statin-myopathy remains unknown.We exposed primary human muscle cell lines (n=4) to a lipophilic (simvastatin) and a hydrophilic More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins.Simvastatin had a much worse effect on the expressome than rosuvastatin, but both statins had a severe impact on cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Eicosanoids rescued the biological function. We also found that muscle cells were very similarly equipped for cholesterol biosynthesis than HepG2 cell.Our data bring a new aspect to the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-3,6 fatty acids could be suitable to prevent or treat statin-myopathy.

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“…Their pharmacological actions and impact on gene expression have been shown to differ [43], [45], [46] and thus, depending on the cells to be treated, the most effective drug has to be determined. Here we show that in case of MPC and MTT, the lipophilic statins fluvastatin, simvastatin, and lovastatin considerably reduced cell proliferation, with simvastatin and fluvastatin showing slightly stronger effects.…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells

et al. 2014

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To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.

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Different statins produce highly divergent changes in gene expression profiles of human hepatoma cells: a pilot study.

Cited by 14 publications

References 32 publications

The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

A prostaglandin alpha F2 analog protects from statin-induced myopathic changes in primary human muscle cells

Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells

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