Resveratrol Suppresses Epithelial-Mesenchymal Transition in GBM by Regulating Smad-Dependent Signaling

Abstract

Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults. Despite continuous improvements in diagnosis and therapeutic method, the prognosis is still far away from expectations. The invasive phenotype of GBM is the main reason for the poor prognosis. Epithelial-mesenchymal transition (EMT) is recognized as a participator in this invasive phenotype. Resveratrol, a natural plant-derived compound, is reported to be able to regulate EMT. In the present study, we used TGF-β1 to induce EMT and aimed to evaluate the effect of resveratrol on EMT and to explore the underline mechanism in GBM. Western blotting was used to detect the expression of EMT-related markers, stemness markers, and Smad-dependent signaling. Wound healing assay and transwell invasion assay were performed to evaluate the migratory and invasive ability of GBM cells. Gliosphere formation assay was used to investigate the effect of resveratrol on the ability of self-renewal. Xenograft experiment was conducted to examine the effect of resveratrol on EMT and Smad-dependent signaling in vivo. Our data validated that resveratrol suppressed EMT and EMT-associated migratory and invasive ability via Smad-dependent signaling in GBM cells. We also confirmed that resveratrol obviously inhibited EMT-induced self-renewal ability of glioma stem cells (GSCs) and inhibited EMT-induced cancer stem cell markers Bmi1 and Sox2, suggesting that resveratrol is able to suppress EMT-generated stem cell-like properties in GBM cells. Furthermore, we also showed the inhibitory effect of resveratrol on EMT in xenograft experiments in vivo. Overall, our study reveals that resveratrol suppresses EMT and EMT-generated stem cell-like properties in GBM by regulating Smad-dependent signaling and provides experimental evidence of resveratrol for GBM treatment.

Bioactive Phenolic Compounds in the Modulation of Central and Peripheral Nervous System Cancers: Facts and Misdeeds

“…The postoperative administration of resveratrol results in a significant prognosis amelioration of rat-advanced orthotopic glioblastoma by reducing growth, inducting apoptosis, and suppressing STAT3 signaling [96]. In addition, resveratrol blocks epithelial-mesenchymal transition in GBM by modulating Smad signaling [97].…”

HCK promotes glioblastoma progression by TGFβ signaling

“…EMT, a trans differentiation process converting epithelial cells into motile mesenchymal cells, is involved in the induction of multiple signaling pathways, and leads to cancer progression [24,25]. Previous studies have indicated that EMT is identified as a mechanism resulting in the invasive phenotype of GBM cells [26,27]. TGFβ signaling pathway plays an important role in regulation of EMT, and is activated in high-grade gliomas, leading to poor prognosis [28].…”

Resveratrol Modulates Transforming Growth Factor-Beta (TGF-β) Signaling Pathway for Disease Therapy: A New Insight into Its Pharmacological Activities

“…It is noteworthy that EMT induction enhances viability via the stimulation of cancer stem cell markers such as Bmi1 and Sox2. By inhibition of the TGF-β/Smad axis, Res not only inhibits EMT and migration, but also interferes with the proliferation and survival of cancer cells [ 179 ]. So, Res can function as a potential modulator of EMT in cancer cells to negatively affect their proliferation and metastasis.…”