Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells

• Published in: Scientific reports 2020-04, Vol.10 (1), p.6361, Article 6361
• Main Authors: Calahorra, Jesús, Martínez-Lara, Esther, Granadino-Roldán, José M., Martí, Juan M., Cañuelo, Ana, Blanco, Santos, Oliver, F. Javier, Siles, Eva
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 38; 38/1; 38/77; 38/89; 631/67/1347; 692/4028/67/1347; 82; Adrenomedullin; AKT protein; Angiogenesis; Bioactive compounds; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; MCF-7 Cells; multidisciplinary; Olive oil; Olive Oil - chemistry; Olive Oil - pharmacology; Oxidative stress; Phenol - chemistry; Phenol - pharmacology; Phenols; Phenylethyl Alcohol - analogs & derivatives; Phenylethyl Alcohol - metabolism; Phenylethyl Alcohol - pharmacology; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins c-akt - genetics; Science; Science (multidisciplinary); Signal Transduction - drug effects; Solid tumors; TOR protein; TOR Serine-Threonine Kinases - genetics; Transcription; Vascular endothelial growth factor
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63417-6

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 i n 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.