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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.

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GLUT1 is the facilitative transporter playing the major role in the internalization of glucose. Basally, GLUT1 resides on vesicles located in a para-golgian area, and is translocated onto the plasmamembrane upon activation of the PI3KC1-AKT pathway. In proliferating cancer cells, which demand a high quantity of glucose for their metabolism, GLUT1 is permanently expressed on the plasmamembrane. This is associated with the abnormal activation of the PI3KC1-AKT pathway, consequent to the mutational activation of PI3KC1 and/or the loss of PTEN. The latter, in fact, could antagonize the phosphorylation of AKT by limiting the availability of Phosphatidylinositol (3,4,5)-trisphosphate. Here, we asked whether PTEN could control the plasmamembrane expression of GLUT1 also through its protein-phosphatase activity on AKT. Experiments of co-immunoprecipitation and in vitro de-phosphorylation assay with homogenates of cells transgenically expressing the wild type or knocked-down mutants (lipid-phosphatase, protein-phosphatase, or both) isoforms demonstrated that indeed PTEN physically interacts with AKT and drives its dephosphorylation, and so limiting the expression of GLUT1 at the plasmamembrane. We also show that growth factors limit the ability of PTEN to dephosphorylate AKT. Our data emphasize the fact that PTEN acts in two distinct steps of the PI3k/AKT pathway to control the expression of GLUT1 at the plasmamembrane and, further, add AKT to the list of the protein substrates of PTEN.

Background/aim Autophagy is a macromolecular degradation process playing a pivotal role in the maintenance of stem-like features and in the morpho-functional remodeling of the tissues undergoing differentiation. In this work we investigated the involvement of autophagy in the osteogenic differentiation of mesenchymal stem cells originated from human gingiva (HGMSC). METHODS: To promote the osteogenic differentiation of HGMSCs we employed resveratrol, a nutraceutical known to modulate autophagy and cell differentiation, together with osteoblastic inductive factors. Osteoblastic differentiation and autophagy were monitored through western blotting and immunofluorescence staining of specific markers. Results We show that HGMSCs can differentiate into osteoblasts when cultured in the presence of appropriate factors and that resveratrol accelerates this process by up-regulating autophagy. The prolonged incubation with dexamethasone, β-glycerophosphate and ascorbic acid induced the osteogenic differentiation of HGMSCc with increased expression of autophagy markers. Resveratrol (1 μM) alone elicited a less marked osteogenic differentiation yet it greatly induced autophagy and, when added to the osteogenic differentiation factors, it provoked a synergistic effect. Resveratrol and osteogenic inductive factors synergistically induced the AMPK-BECLIN-1 pro-autophagic pathway in differentiating HGMSCs, that was thereafter downregulated in osteoblastic differentiated cells. Pharmacologic inhibition of BECLIN-1-dependent autophagy precluded the osteogenic differentiation of HGMSCs. Conclusions Autophagy modulation is instrumental for osteoblastic differentiation of HGMSCs. The present findings can be translated into the regenerative cell therapy of maxillary / mandibular bone defects. Graphical abstract