miRNA Modulation and Antitumor Activity by the Extra-Virgin Olive Oil Polyphenol Oleacein in Human Melanoma Cells

Sara Carpi; Beatrice Polini; Clementina Manera; Maria Digiacomo; Jasmine Esposito Salsano; Marco Macchia; Egeria Scoditti; Paola Nieri

doi:10.3389/fphar.2020.574317

miRNA Modulation and Antitumor Activity by the Extra-Virgin Olive Oil Polyphenol Oleacein in Human Melanoma Cells

Front Pharmacol. 2020 Sep 23:11:574317. doi: 10.3389/fphar.2020.574317. eCollection 2020.

Authors

Sara Carpi^{1

2}, Beatrice Polini¹, Clementina Manera^{2

3}, Maria Digiacomo^{2

3}, Jasmine Esposito Salsano⁴, Marco Macchia^{2

3}, Egeria Scoditti⁵, Paola Nieri^{1

2}

Affiliations

¹ Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Pisa, Pisa, Italy.
² Interdepartmental Research Center "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
³ Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, Pisa, Italy.
⁴ Doctoral School in Life Sciences, University of Siena, Siena, Italy.
⁵ Laboratory of Vascular Biology and Nutrigenomics, National Research Council (CNR) Institute of Clinical Physiology (IFC), Lecce, Italy.

Abstract

Extra-virgin olive oil (EVOO) polyphenols contribute to Mediterranean diet health-promoting properties. One of the most abundant secoiridoid present in EVOO, Oleacein (OA), demonstrated anticancer activity against several tumors. Nevertheless, its role against melanoma has not still investigated. This study aimed at determining in vitro the antimelanoma activity of OA and the relative mechanism of action. OA induced cell growth inhibition in 501Mel melanoma cells with an IC50 in the low micromolar range of concentrations. Moreover, an OA concentration approximating the IC50 induced G1/S phase arrest, DNA fragmentation, and downregulation of genes encoding antiapoptotic (BCL2 and MCL1) and proproliferative (c-KIT, K-RAS, PIK3R3, mTOR) proteins, while increased transcription levels of the proapoptotic protein BAX. Concordantly, OA increased the levels of miR-193a-3p (targeting MCL1, c-KIT and K-RAS), miR-193a-5p (targeting PIK3R3 and mTOR), miR-34a-5p (targeting BCL2 and c-KIT) and miR-16-5p (miR-16-5p targeting BCL2, K-RAS and mTOR), while decreased miR-214-3p (targeting BAX). These modulatory effects might contribute to the inhibition of 501Mel melanoma cell growth observed after treatment with an olive leaves-derived formulation rich in OA, with potential application against in situ cutaneous melanoma. Altogether, these results demonstrate the ability of OA to contrast the proliferation of cutaneous melanoma cells through the transcriptional modulation of relevant genes and microRNAs, confirming the anticancer potential of EVOO and suggesting OA as a chemopreventive agent for cancer disease therapy.

Keywords: BCL2; apoptosis; extra-virgin olive oil; mTOR; melanoma; microRNA; oleacein; polyphenols.