A dose-response curve for gamma-radiation-induced neoplastic transformation of HeLa x skin fibroblast human hybrid cells over the dose range 0.1 cGy to 1 Gy is presented. In the experimental protocol used, the spontaneous (background) frequency of neoplastic transformation of sham-irradiated cultures was compared to that of cultures which had been irradiated with (137)Cs gamma radiation and either plated immediately or held for 24 h at 37 degrees C prior to plating, for assay for neoplastic transformation. The pooled data from a minimum of three repeat large-scale experiments at each dose demonstrated a reduced transformation frequency for the irradiated compared to the sham-irradiated cells for doses of 0.1, 0.5, 1, 5 and 10 cGy for the delayed-plating arm. The probability of this happening by chance is given by 1/2(n), where n is the number of observations (5); i.e., 1/32 congruent with 0.031. This is indicative of an adaptive response against spontaneous neoplastic transformation at least up to a dose of 10 cGy of gamma radiation. The high-dose data obtained at 30 and 50 cGy and 1 Gy showed a good fit to a linear extrapolation through the sham-irradiated, zero-dose control. The delayed-plating data at 10 cGy and below showed a statistically significant divergence from this linear extrapolation.

Opening of voltage dependent anion channels (VDAC) by the erastin-like compound X1 and the multikinase inhibitor sorafenib promotes oxidative stress and mitochondrial dysfunction in hepatocarcinoma cells. Here, we hypothesized that X1 and sorafenib induce mitochondrial dysfunction by increasing ROS formation and activating c-Jun N-terminal kinases (JNKs), leading to translocation of activated JNK to mitochondria. Both X1 and sorafenib increased production of reactive oxygen species (ROS) and activated JNK. X1 and sorafenib caused a drop in mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, after 60 min. Mitochondrial depolarization after X1 and sorafenib occurred in parallel with JNK activation, increased superoxide (O 2•− ) production, decreased basal and oligomycin sensitive respiration, and decreased maximal respiratory capacity. Increased production of O 2 •− after X1 or sorafenib was abrogated by JNK inhibition and antioxidants. S3QEL specific inhibitor of site IIIQ o, at Complex III prevented depolarization induced by X1. JNK inhibition by JNK inhibitors VIII and SP600125 also prevented mitochondrial depolarization. After X1, activated JNK translocated to mitochondria as assessed by proximity ligation assays.

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

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arachidic) consistent with the changes observed in liver's metabolome. Higher liver AMP levels in HCR vs. LCR suggest activation of AMPK signaling, in agreement with the enhanced autophagy/mitophagy observed in HCR. Importantly, the higher relative LCR/HCR fold-changes of acetylated intermediates, in both liver and serum, agrees with the idea of widespread increased acetylation, compatible with the higher concentration of AcCoA measured in cardiomyocytes from LCR vs. HCR. Metabolomics reveal systemic, organ-concerted (liver-serum-heart), metabolic remodeling compatible with higher energetic performance, better preserved mitochondrial turnover, preferential lipid oxidation, and improved control of acetylation in HCR leading to extended longevity and better functional capacity.