Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

被引:31
作者
Christie, Charleston F. [1 ]
Fang, Diana [1 ]
Hunt, Elizabeth G. [1 ]
Morris, Morgan E. [1 ]
Rovini, Amandine [1 ]
Heslop, Kareem A. [1 ]
Beeson, Gyda C. [1 ]
Beeson, Craig C. [1 ]
Maldonado, Eduardo N. [1 ,2 ]
机构
[1] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Drug Discovery Bldg 506,70 President St-MSC 139, Charleston, SC 29425 USA
[2] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA
基金
美国国家卫生研究院;
关键词
glycolysis; lovastatin; mitochondrial membrane potential; oxidative phosphorylation; simvastatin; CYCLE ARREST; HEPATOCELLULAR-CARCINOMA; SIMVASTATIN; APOPTOSIS; LOVASTATIN; ATORVASTATIN; INHIBITION; MYOPATHY; RISK; ATP;
D O I
10.1096/fj.201802723R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Statins, widely used to treat hypercholesterolemia, inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of de novo cholesterol (Chol) synthesis. Statins have been also reported to slow tumor progression. In cancer cells, ATP is generated both by glycolysis and oxidative phosphorylation. Mitochondrial membrane potential (Delta Psi), a readout of mitochondrial metabolism, is sustained by the oxidation of respiratory substrates in the Krebs cycle to generate NADH and flavin adenine dinucleotide, which are further oxidized by the respiratory chain. Here, we studied the short-term effects of statins (3-24 h) on mitochondrial metabolism on cancer cells. Lovastatin (LOV) and simvastatin (SIM) increased Delta Psi in HepG2 and Huh7 human hepatocarcinoma cells and HCC4006 human lung adenocarcinoma cells. Mitochondrial hyperpolarization after LOV and SIM was dose and time dependent. Maximal increase in Delta Psi occurred at 10 mu M and 24 h for both statins. The structurally unrelated atorvastatin also hyperpolarized mitochondria in HepG2 cells. Cellular and mitochondrial Chol remained unchanged after SIM. Both LOV and SIM decreased basal respiration, ATP-linked respiration, and ATP production. LOV and SIM did not change the rate of lactic acid production. In summary, statins modulate mitochondrial metabolism in cancer cells independently of the Chol content in cellular membranes without affecting glycolysis.-Christie, C. F., Fang, D., Hunt, E. G., Morris, M. E., Rovini, A., Heslop, K. A., Beeson, G. C., Beeson, C. C., Maldonado, E. N. Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content.
引用
收藏
页码:8186 / 8201
页数:16
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