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Hypoxia is a common feature of most solid tumors, one that favors tumor progression and limits treatment effectiveness. Targeting hypoxia has long been a goal in cancer therapy, by identifying factors that reverse or ameliorate the effects of hypoxia on cancer cells. We, and others, have shown that β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. We have further shown that non-cytotoxic concentrations of BCP affect cholesterol and lipid biosynthesis in hypoxic hBrC cells at both transcriptional and translational levels. This led us to hypothesize that BCP may reverse the hypoxic phenotype in hBrC cells. To test this, we determined the effect of BCP on hypoxic sensitive pathways, including oxygen consumption, glycolysis, oxidative stress, cholesterol and fatty acid biosynthesis, and ERK activation. While each of these studies revealed new information on the regulation by hypoxia and BCP, only the lipidomic studies showed reversal of hypoxic-dependent effects by BCP. These later studies showed that hypoxia-treated samples lowered monounsaturated fatty acid levels, shifting the saturation ratios of the fatty acid pools. This signature was ameliorated by sub-lethal concentrations of BCP, possibly through an effect on the C:16 fatty acid saturation ratios. This is consistent with BCP-induced upregulation of the stearoyl-CoA desaturase (SCD) gene, observed previously. This suggests that BCP may interfere with the lipid signature modulated by hypoxia which could have consequences for membrane biosynthesis or composition, both of which are important for cell replication.