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

Jesús Calahorra,Santos Blanco,Juan M Martí,Esther Martínez-Lara,F Javier Oliver,Ana Cañuelo,Eva Siles,José M Granadino-Roldán

doi:10.1038/s41598-020-63417-6

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.

Highlights

Olive oil intake has been linked with a lower incidence of breast cancer
Our results indicate that in hypoxic MCF-7 breast cancer cells, HT decreases the expression of HIF-1α, an effect probably linked to its antioxidant action and to the down-regulation of the PI3K/Akt/mTOR pathway
In a previous study we demonstrated that HT, the main extra-virgin olive oil (EVOO) phenolic compound in olive oil and a recognized nutraceutical, modulates the oxidative response to hypoxia of MCF-7 cells[23], a breast cancer cell line consistently used in the literature to assess the effect of this phenol

Summary

Introduction

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-1α is dependent on the expression and activity of Poly(ADP-ribose) polymerase-1 (PARP-1)[13,14], a nuclear, zinc-finger, DNA-binding protein activated in response to oxidative and nitrosative stress This enzyme plays an important role in a number of processes such as DNA repair, chromatin www.nature.com/scientificreports remodeling, transcription or regulation of the cell cycle, among others[15]. We have recently described that hypoxia modulates the antioxidant effect of HT in MCF-7 breast cancer cells[23] With this background, and considering the importance of hypoxia and HIF-1 in breast cancer progression and response to anticancer treatments, the aim of the present study is to investigate the effect of HT in the expression and transcriptional activity of this protein. Our results indicate that in hypoxic MCF-7 breast cancer cells, HT decreases the expression of HIF-1α, an effect probably linked to its antioxidant action and to the down-regulation of the PI3K/Akt/mTOR pathway. We show that at high concentrations HT can even act as an AHR agonist

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