Resveratrol Induces Differentiation Markers Expression in Anaplastic Thyroid Carcinoma via Activation of Notch1 Signaling and Suppresses Cell Growth

Abstract

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive malignancy with undifferentiated features, for which conventional treatments, including radioactive iodine ablation, are usually not effective. Recent evidence suggests that the Notch1 pathway is important in the regulation of thyroid cancer cell growth and expression of thyrocyte differentiation markers. However, drug development targeting Notch1 signaling in ATC remains largely underexplored. Previously, we have identified resveratrol out of over 7,000 compounds as the most potent Notch pathway activator using a high-throughput screening method. In this study, we showed that resveratrol treatment (10–50 μM) suppressed ATC cell growth in a dose-dependent manner for both HTh7 and 8505C cell lines via S phase cell cycle arrest and apoptosis. Resveratrol induced functional Notch1 protein expression and activated the pathway by transcriptional regulation. In addition, the expression of thyroid-specific genes including TTF1, TTF2, Pax8 and sodium iodide symporter (NIS) were up-regulated in both ATC cell lines with resveratrol treatment. Notch1 siRNA interference totally abrogated the induction of TTF1 and Pax8 but not of TTF2. Moreover, Notch1 silencing by siRNA decreased resveratrol-induced NIS expression. In summary, our data indicate that resveratrol inhibits cell growth and enhances re-differentiation in ATC cells dependent upon the activation of Notch1 signaling. These findings provide the first documentation for the role of resveratrol in ATC re-differentiation, suggesting that activation of Notch1 signaling could be a potential therapeutic strategy for ATC patients, and thus warrants further clinical investigation.

Resveratrol Inhibits Phenotypic Switching of Neointimal Vascular Smooth Muscle Cells After Balloon Injury Through Blockade of Notch Pathway

“…Emerging cancer studies have suggested that RSV can antagonize cell growth through activation of intracellular Notch-1. 35,36 In contrast, our study indicates that inhibitory effects of RSV on serum-induced cell proliferation and migration mainly through inactivation of Notch pathway. Furthermore, blockade on Notch-1 intracellular domain release is the most important target.…”

Tumor-Suppressor Role of Notch3 in Medullary Thyroid Carcinoma Revealed by Genetic and Pharmacological Induction

“…To quantify apoptosis, cells (2×10 5 ) were treated with media or 0.2, 0.5, or 1 µg/ml doxycycline for 96 hours and harvested using non-enzymatic cell dissociation solution, Cellstripper (Cellgro). Both floating and adherent cells were collected, stained with PE Annexin V and 7 AAD fluorescein solutions (BD Pharmingen) for 15 minutes at room temperature in the dark, and flow cytometry was performed as described previously (27). Data was analyzed using FlowJo V5.0 (Tree Star, Inc.).…”

Cancer stem-like cells and thyroid cancer

“…Recent studies have shown that the novel Notch1 activator, chrysin, inhibits tumor growth in ATC both in vitro and in vivo (Yu et al 2013a). Resveratrol inhibits cell growth and enhances redifferentiation in ATC cells, dependent upon the activation of Notch1 signaling (Yu et al 2013b). It has recently been shown that Notch signaling is activated in endothelial cells, promoting angiogenesis after interaction with cancer cells in head and neck squamous cell carcinomas.…”