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

Abstract

Statins, widely used to treat hypercholesterolemia, inhibit the 3‐hydroxy‐3‐methylglutary1‐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 (ΔΨ), 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 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 ΔΨ occurred at 10 µM 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. FASEB J. 33, 8186–8201 (2019). http://www.fasebj.org

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…Additionally, Sim, is a cholesterol-lowering agent, and recently has also been reported to participate in the suppression of glycolysis and Sora resistance. Christie et al found that statins can partially block the utilization of glycolytic ATP [46]. Huang et al found that the combination of pitavastatin and paclitaxel can significantly decrease the glycolytic rate in renal carcinoma [47].…”

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

“…Mitochondrial hyperpolarization represents an early and reversible step in T cell activation and apoptosis [79]. Transient high ΔΨ m values have also been described by synthetic cannabinoids in human proximal tubule cells [80], by statins (lovastatin and simvastatin), which increased the ΔΨ m in HepG2 and Huh7 human hepatocarcinoma cells and HCC4006 human lung adenocarcinoma cells [81], and by honokiol, which induced in bladder cancer cells and increase of ΔΨ m and ROS formation, and at high doses apoptotic cell death [82]. Hyperpolarization of ΔΨ m was furthermore shown with protamine sulfate [83] and graphene oxide (a marker for air pollution) [84].…”

Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma

“…Atorvastatin also induced autophagy and inhibited proliferation on prostate cancer cells through up-regulation of miR-182 [19]. Atorvastatin has been identified through modulating mitochondrial metabolism to interfere cancer process [20]. However, any other mechanism implicated in the anti-tumor effect of atorvastatin has not been clearly elucidated.…”