Abstract
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults. GBM remains one of the most fatal and least successfully treated solid tumors: current therapies provide a median survival of 12–15 months after diagnosis, due to the high recurrence rate. Glioma Stem Cells (GSCs) are believed to be the real driving force of tumor initiation, progression and relapse. Therefore, better therapeutic strategies GSCs-targeted are needed. Resveratrol is a polyphenolic phytoalexin found in fruits and vegetables displaying pleiotropic health benefits. Many studies have highlighted its chemo-preventive and chemotherapeutic activities in a wide range of solid tumors. In this work, we analyzed the effects of Resveratrol exposure on cell viability, proliferation and motility in seven GSC lines isolated from GBM patients. For the first time in our knowledge, we investigated Resveratrol impact on Wnt signaling pathway in GSCs, evaluating the expression of seven Wnt signaling pathway-related genes and the protein levels of c-Myc and β-catenin. Finally, we analyzed Twist1 and Snail1 protein levels, two pivotal activators of epithelial-mesenchymal transition (EMT) program.Results showed that although response to Resveratrol exposure was highly heterogeneous among GSC lines, generally it was able to inhibit cell proliferation, increase cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway and the EMT activators. Treatment with Resveratrol may represent a new interesting therapeutic approach, in order to affect GSCs proliferation and motility, even if further investigations are needed to deeply understand the GSCs heterogeneous response.
Highlights
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults [1]
Results showed that response to Resveratrol exposure was highly heterogeneous among Glioma Stem Cells (GSCs) lines, generally it was able to inhibit cell proliferation, increase cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway and the epithelial-mesenchymal transition (EMT) activators
Metabolic activity values were almost unchanged in all GSC lines after 24 hs of treatment; on the contrary after 48 hs, GBM2, G179 and GBM04 cell lines showed a significant decrease in metabolic activity (p
Summary
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults [1]. The highly migratory capacity of GSCs is another crucial factor that results in an invasive spread of GBM in different areas of the brain, making this tumor extremely difficult to eradicate [1]. Resveratrol (trans-3,4’,5 tryhidrostilbene) (RSV) is a natural polyphenolic phytoalexin found in fruits and vegetables, acting as a phytoestrogen and displaying pleiotropic health benefits. This compound has received considerable attention over the last decades, especially for its anti-oxidant and anti-inflammatory properties, which can explain its efficacy in treating cardiovascular diseases and its neuroprotective effect, due to its ability to cross the blood brain barrier [7]. RSV beneficial effects involve the modulation of a huge number of molecular targets, including the activation of enzymes such as sirtuin (SIRT1), a NAD-dependent deacetylase, which can influence chromatin remodeling and gene expression [8]
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