Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth. Mol Cancer Ther 2013 Jul;12(7):1276-87
Date
04/19/2013Pubmed ID
23594881Pubmed Central ID
PMC3707971DOI
10.1158/1535-7163.MCT-12-0841Scopus ID
2-s2.0-84880047940 (requires institutional sign-in at Scopus site) 90 CitationsAbstract
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 μmol/L) 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) was upregulated 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 redifferentiation in ATC cells dependent upon the activation of Notch1 signaling. These findings provide the first documentation for the role of resveratrol in ATC redifferentiation, suggesting that activation of Notch1 signaling could be a potential therapeutic strategy for patients with ATC and thus warrants further clinical investigation.
Author List
Yu XM, Jaskula-Sztul R, Ahmed K, Harrison AD, Kunnimalaiyaan M, Chen HMESH terms used to index this publication - Major topics in bold
AnimalsAnticarcinogenic Agents
Antigens, Differentiation
Apoptosis
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Humans
Male
Mice
Random Allocation
Receptor, Notch1
Signal Transduction
Stilbenes
Thyroid Carcinoma, Anaplastic
Thyroid Neoplasms
Xenograft Model Antitumor Assays