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Sci Rep ; 10(1): 6361, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32286485

ABSTRACT

Olive oil intake has been linked with a lower incidence of breast cancer. Hypoxic microenvironment in solid tumors, such as breast cancer, is known to play a crucial role in cancer progression and in the failure of anticancer treatments. HIF-1 is the foremost effector in hypoxic response, and given that hydroxytyrosol (HT) is one of the main bioactive compounds in olive oil, in this study we deepen into its modulatory role on HIF-1. Our results in MCF-7 breast cancer cells demonstrate that HT decreases HIF-1α protein, probably by downregulating oxidative stress and by inhibiting the PI3K/Akt/mTOR pathway. Strikingly, the expression of HIF-1 target genes does not show a parallel decrease. Particularly, adrenomedullin and vascular endothelial growth factor are up-regulated by high concentrations of HT even in HIF-1α silenced cells, pointing to HIF-1-independent mechanisms of regulation. In fact, we show, by in silico modelling and transcriptional analysis, that high doses of HT may act as an agonist of the aryl hydrocarbon receptor favoring the induction of these angiogenic genes. In conclusion, we suggest that the effect of HT in a hypoxic environment is largely affected by its concentration and involves both HIF-1 dependent and independent mechanisms.


Subject(s)
Breast Neoplasms/drug therapy , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Olive Oil/pharmacology , Phenol/pharmacology , Phenylethyl Alcohol/analogs & derivatives , Breast Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Olive Oil/chemistry , Phenol/chemistry , Phenylethyl Alcohol/metabolism , Phenylethyl Alcohol/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/genetics
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