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Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content
Author(s) -
Christie Charleston F.,
Fang Diana,
Hunt Elizabeth G.,
Morris Morgan E.,
Rovini Amandine,
Heslop Kareem A.,
Beeson Gyda C.,
Beeson Craig C.,
Maldonado Eduardo N.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802723r
Subject(s) - lovastatin , mitochondrion , simvastatin , oxidative phosphorylation , cancer cell , glycolysis , biochemistry , metabolism , chemistry , biology , endocrinology , medicine , cholesterol , cancer
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). www.fasebj.org