Statins Use and Cancer: An Update

Zaleska, Martyna; Możeńska, Olga; Bil, Jacek

doi:10.2217/fon-2017-0543

Cited by 45 publications

(40 citation statements)

References 94 publications

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“…Importantly, lovastatin inhibits cell proliferation and migration in both ER positive and triple negative breast cancer cells, possibly due to a decrease in intracellular cholesterol levels [39], and cholesterol is able to rescue these effects of lovastatin. The anticancer effects of statins have been shown to involve multiple molecular pathways, including inhibition of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) [40,41]. the Neverthless, the current study demonstrates thatin the presence of lovastatin, addition of cholesterol is able to restore the inhibitory effects of lovastatin on cell proliferation and migration of MDA-MB-231 cells via the ERRα pathway, while ERRα protein levels remain unchanged.…”

Section: Discussionmentioning

confidence: 64%

“…Also, they have shown that F232 and L228 of ERRα possibly make important hydrophobic contacts with cholesterol [29]. A limitation of our study is that cholesterol lowering drugs like statins have been reported to have cholesterol-independent effects [40,41]. Unfortunately, there are no known cholesterol depleting agents that do not exhibit cholesterol-independent effects.…”

Section: Discussionmentioning

confidence: 87%

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Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells

Ghanbari

Mader

Philip

2020

Cells

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Breast cancer is the 2nd leading cause of cancer-related death among women. Increased risk of breast cancer has been associated with high dietary cholesterol intake. However, the underlying mechanisms are not known. The nuclear receptor, estrogen-related receptor alpha (ERRα), plays an important role in breast cancer cell metabolism, and its overexpression has been linked to poor survival. Here we identified cholesterol as an endogenous ligand of ERRα by purification from human pregnancy serum using a GST-ERRα affinity column and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We show that cholesterol interacts with ERRα and induces its transcriptional activity in estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) cells. In addition, we show that cholesterol enhances ERRα-PGC-1α interaction, induces ERRα expression itself, augments several metabolic target genes of ERRα, and increases cell proliferation and migration in both ER+ and TNBC cells. Furthermore, the stimulatory effect of cholesterol on metabolic gene expression, cell proliferation, and migration requires the ERRα pathway. These findings provide a mechanistic explanation for the increased breast cancer risk associated with high dietary cholesterol and possibly the pro-survival effect of statins in breast cancer patients, highlighting the clinical relevance of lowering cholesterol levels in breast cancer patients overexpressing ERRα.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 87%

Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells

Ghanbari

Mader

Philip

2020

Cells

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“…Currently, statins are in use for preventing or treating cancer patients with prostate (206), breast (207), lung (208), liver (209), and other cancers (210,211). The safety, efficacy and mortality benefits of statins have been assessed both alone and in combination therapy in clinical cancer patients studies (212)(213)(214).…”

Section: Targeting Hmgcr In Clinical Cancer Therapymentioning

confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

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Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

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“…Statins may exert their anticancer effect through several molecular mechanisms: via lowering protein prenylation, reducing tumor cell proliferation and migration, inhibiting rat sarcoma (Ras) signaling, inducing apoptosis through inhibition of Akt phosphorylation and consequently mammalian target of rapamycin (mTOR) down-regulation and other pleiotropic effects on cellular level ( 57 , 58 ).…”

Section: General Conceptmentioning

confidence: 99%

Cholesterol as an Endogenous ERRα Agonist: A New Perspective to Cancer Treatment

et al. 2018

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The estrogen-related receptors (ERRs) are important members of nuclear receptors which contain three isoforms (α, β, and γ). ERRα is the best-characterized isoform expressed mainly in high-energy demanding tissues where it preferentially works in association with the peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and PGC-1β. ERRα together with its cofactors modulates cellular metabolism, supports the growth of rapidly dividing cells, directs metabolic programs required for cell differentiation and maintains cellular energy homeostasis in differentiated cells. In cancer cells, the functional association between ERRα and PGC-1s is further influenced by oncogenic signals and induces metabolic programs favoring cell growth and proliferation as well as tumor progression. Recently, cholesterol has been identified as a natural ERRα ligand using a combined biochemical strategy. This new finding highlighted some important physiological aspects related to the use of cholesterol-lowering drugs such as statins and bisphosphonates. Even more meaningful is the link between increased cholesterol levels and certain cancer phenotypes characterized by an overexpressed ERRα such as mammary, prostatic, and colorectal cancers, where the metabolic adaptation affects many cancer processes. Moreover, high-energy demanding cancer-related processes are strictly related to the cross-talk between tumor cells and some key players of tumor microenvironment, such as tumor-associated macrophage that fuels cancer progression. Some evidence suggests that high cholesterol content and ERRα activity favor the inflammatory environment by the production of different cytokines. In this review, starting from the most recent observations on the physiological role of the new signaling activated by the natural ligand of ERRα, we propose a new hypothesis on the suitability to control cholesterol levels as a chance in modulating ERRα activity in those tumors in which its expression and activity are increased.

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Statins Use and Cancer: An Update

Cited by 45 publications

References 94 publications

Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells

Cholesterol as an Endogenous Ligand of ERRα Promotes ERRα-Mediated Cellular Proliferation and Metabolic Target Gene Expression in Breast Cancer Cells

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Cholesterol as an Endogenous ERRα Agonist: A New Perspective to Cancer Treatment

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