title: Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy.
abstract: Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer-associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. © 2016 Wiley Periodicals, Inc.
authors: Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Alessandra
authors: A
authors: Ferraresi
authors: Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Suratchanee
authors: S
authors: Phadngam
authors: Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Federica
authors: F
authors: Morani
authors: Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Alessandra
authors: A
authors: Galetto
authors: Unit of Oncology, Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Oscar
authors: O
authors: Alabiso
authors: Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia, Biella, Italy.
authors: Giovanna
authors: G
authors: Chiorino
authors: Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors: Ciro
authors: C
authors: Isidoro
mesh_terms: D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000235:genetics
chemical_list: D000071186:Beclin-1; C117386:DIRAS3 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D013267:Stilbenes; D020741:rho GTP-Binding Proteins; D000077185:Resveratrol
keywords: Resveratrol; autophagy; cell migration; microRNA; ovarian cancer