Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

Crosbie, Jon; Magnussen, Marc; Dornbier, Ryan; Iannone, Alexandra; Steele, Timothy A.

doi:10.1186/2050-7771-1-33

Cited by 29 publications

(24 citation statements)

References 20 publications

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“…The second correlated expression profile with statin use was a signature of improved prognosis among pediatric acute myeloid leukemia patients (AML). In tumor cell lines, statins were shown to inhibit the growth of acute myeloid leukemia cells [ 51 ], to synergistically increase the killing of the human erythroleukemia cell line K562 by the chemotherapeutic agent cytosine arabinoside [ 52 ], and to inhibit the proliferation and cytotoxicity of a human leukemic natural killer cell line [ 53 ]. The third correlated signature with statin use was a signature of Parkinson’s disease (PD) patients when compared with healthy or neurodegenerative disease controls[ 54 ].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Statins on Blood Gene Expression in COPD

et al. 2015

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BackgroundCOPD is currently the fourth leading cause of death worldwide. Statins are lipid lowering agents with documented cardiovascular benefits. Observational studies have shown that statins may have a beneficial role in COPD. The impact of statins on blood gene expression from COPD patients is largely unknown.ObjectiveIdentify blood gene signature associated with statin use in COPD patients, and the pathways underpinning this signature that could explain any potential benefits in COPD.MethodsWhole blood gene expression was measured on 168 statin users and 451 non-users from the ECLIPSE study using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and surrogate variables. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser.Results25 genes were differentially expressed between statin users and non-users at an FDR of 10%, including LDLR, CXCR2, SC4MOL, FAM108A1, IFI35, FRYL, ABCG1, MYLIP, and DHCR24. The 25 genes were significantly enriched in cholesterol homeostasis and metabolism pathways. The resulting gene signature showed correlation with Huntington’s disease, Parkinson’s disease and acute myeloid leukemia gene signatures.ConclusionThe blood gene signature of statins’ use in COPD patients was enriched in cholesterol homeostasis pathways. Further studies are needed to delineate the role of these pathways in lung biology.

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Section: Discussionmentioning

confidence: 99%

The Effect of Statins on Blood Gene Expression in COPD

et al. 2015

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“…Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which is the rate-limiting enzyme in the melavonate pathway; a pathway producing a range of cell signalling molecules with the potential to regulate oncogenesis. This is supported by strong laboratory evidence that statins induce anticarcinogenic effects on cell proliferation and survival in various cell lines [1][2][3][4] , and reduce tumour growth in a range of in vivo models [5][6][7][8][9][10] .…”

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confidence: 83%

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

Carter

Vithayathil

Kar

et al. 2020

Preprint

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Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

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“…These data strongly suggest that in our experimental nude mouse model, the atorvastatin-induced control of subcutaneous melanoma growth is dependent on NK cell activity. Moreover, previous studies of the anti-inflammatory effects of atorvastatin [23,24] suggest that in our experiments the atorvastatininduced increase in activated (CD69 + ) NK cells is not linked to a direct effect of atorvastatin on NK cells but is more likely due to atorvastatininduced MICA overexpression in melanoma cells. However, intraperitoneal statin injections induce systemic disruptions, which could also interfere with the innate anti-melanoma immune response by acting on Tγδ cells.…”

Section: Discussionmentioning

confidence: 70%

“…Our previous papers have shown that inhibition of RhoA/ROCK activity favors anti-melanoma immune response through MHC-class I, costimulatory molecules and FasL overexpression on melanoma cells membrane [3][4][5]. Furthermore, as previously described, the inhibition of ROCK activity reduces melanoma cells migration, invasion and metastases [23][24][25][26][27]. Consequently Atorvastatin pre-treatment of WM-266-4 cells at 1 μM mainly reduces local tumor growth and metastasis development through MICA overexpression and NK cell activity.…”

Section: Discussionmentioning

confidence: 98%

Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

Teiti¹,

Sarrabayrouse²

2016

Immunother Open Acc

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Statins, 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are pleiotropic pharmacological inhibitors, which block the mevalonate synthesis pathway. They are widely used as hypocholesterolemic agents and have shown protective effects against cancers.Our previous data showed that statin treatment induced MHC class I chain-related protein A (MICA) membrane overexpression in human melanoma cells, which increased their sensitivity to NK cell cytotoxicity and thus the inhibition of tumor development. MICA is a ligand of the NK cell activating receptor NKG2D. This receptor is essential for NK cell control of tumor development and it has the unique property of being able to recognize tumor cells of both murine and human origin.Here, using atorvastatin and the WM-266-4 melanoma cell line, we first confirmed that statin treatment enhances MICA membrane expression and decreases local tumor growth and pulmonary metastasis implantation in vivo. Furthermore our new experiments showed that atorvastatin intraperitoneal repeated injections induced a reduction of tumor growth following subcutaneous implantation of untreated WM 266-4 cells into NMRI nude mice and favored the innate anti-melanoma immune response by increasing splenic NK cell concentration and activation. This report confirms that statins could become effective pharmacological agents for melanoma immunotherapy.

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Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

Cited by 29 publications

References 20 publications

The Effect of Statins on Blood Gene Expression in COPD

The Effect of Statins on Blood Gene Expression in COPD

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

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