Statin-mediated inhibition of cholesterol synthesis induces cytoprotective autophagy in human leukemic cells

Vilimanovich, Urosh; Bošnjak, Mihajlo; Bogdanović, Andrija; Marković, Ivanka; Isaković, Aleksandra; Kravić-Stevović, Tamara; Mirčić, Aleksandar; Trajkovič, Vladimir; Bumbaširević, Vladimir

doi:10.1016/j.ejphar.2015.09.004

Cited by 51 publications

(44 citation statements)

References 59 publications

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“…In U251 cells treated with 6 μ m of Simva for 24 h, autophagy was induced and could be reversed by the addition of 100 μ m of MEV, again implicating the involvement of the MEV cascade in statin‐mediated autophagy . In human leukemia cells treated with 3–6 μ m Simva for 24–72 h, induction of autophagy flux appeared to be mediated by statin‐mediated inhibition of CH production, but not FPP or GGPP synthesis . In contrast to our results, all of the above studies used measurements of LC3II levels, and/or GFP‐LC3 in imaging, and/or TEM and claimed statin‐mediated induction of the autophagy pathway.…”

Section: Discussioncontrasting

confidence: 94%

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Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

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Section: Discussioncontrasting

confidence: 94%

“…Removal of FBS from the media would have caused starvation, which is a known inducer of autophagy [64,65]. A previous study had indicated that treatment of myelogenous leukemia cell line K562 with high doses (6 lM) of Simva reduced cellular CH content, but this was observed only after 48 h of incubation [66].…”

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confidence: 99%

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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“…Conversely, depletion of cholesterol or inhibition of cholesterol synthesis induces autophagy (127,128). In vitro fusion assays showed that altered membrane composition of autophagosomes and lysosomes isolated from lipid-loaded fibroblasts or high fat fed mouse liver inhibits the fusion between these organelles, which could account for the impaired autophagy in many lipid-induced lysosomal disorders (69).…”

Section: Regulation Of Lysosomal Function By Lipidsmentioning

confidence: 99%

Lipids, lysosomes, and autophagy

Jaishy

Abel

2016

Journal of Lipid Research

173

139

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Lipids are essential components of a cell providing energy substrates for cellular processes, signaling intermediates, and building blocks for biological membranes. Lipids are constantly recycled and redistributed within a cell. Lysosomes play an important role in this recycling process that involves the recruitment of lipids to lysosomes via autophagy or endocytosis for their degradation by lysosomal hydrolases. The catabolites produced are redistributed to various cellular compartments to support basic cellular function. Several studies demonstrated a bidirectional relationship between lipids and lysosomes that regulate autophagy. While lysosomal degradation pathways regulate cellular lipid metabolism, lipids also regulate lysosome function and autophagy. In this review, we focus on this bidirectional relationship in the context of dietary lipids and provide an overview of recent evidence of how lipid-overload lipotoxicity, as observed in obesity and metabolic syndrome, impairs lysosomal function and autophagy that may eventually lead to cellular dysfunction or cell death.

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“…Resveratrol has been shown to stimulate autophagy through the activation of the deacetylase SIRT1 [53], but could also directly inhibit mTOR kinase activity through ATP competition (Park 2016 Scientific reports) whereas spermidine is thought to act as an inhibitor of acetylases [52]. The observed autophagic response induces by statins seems associated with the reduction of phosphorylated Akt levels accompanied by a decrease in the activation of mTOR and its substrate ribosomal p70S6 kinase [68]. …”

Section: Induction Of Autophagy In Mouse Modelsmentioning

confidence: 99%

Methods for Measuring Autophagy in Mice

Moulis

Vindis

2017

Cells

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Autophagy is a dynamic intracellular process that mediates the degradation of damaged cytoplasmic components by the lysosome. This process plays important roles in maintaining normal cellular homeostasis and energy balance. Measuring autophagy activity is critical and although the determination of autophagic flux in isolated cells is well documented, there is a need to have reliable and quantitative assays to evaluate autophagy in whole organisms. Because mouse models have been precious in establishing the functional significance of autophagy under physiological or pathological conditions, we present in this chapter a compendium of the current available methods to measure autophagy in mice, and discuss their advantages and limitations.

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Statin-mediated inhibition of cholesterol synthesis induces cytoprotective autophagy in human leukemic cells

Cited by 51 publications

References 59 publications

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Lipids, lysosomes, and autophagy

Methods for Measuring Autophagy in Mice

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