Resveratrol Induces Notch2-Mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer
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Currently, complete surgical resection is the only curative option for medullary thyroid cancer (MTC). Previous work has shown the Notch pathway is a potent tumor suppressor in MTC and that resveratrol activates the Notch pathway in carcinoid cancer, a related neuroedocrine malignancy. In this study, we hypothesized that the effects observed on carcinoid cells could be extended to MTC.
MTC cells treated with varying doses of resveratrol were assayed for viability by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Western blot analysis for achaete-scute complex-like 1 (ASCL1), chromogranin A (CgA), full-length and cleaved caspase 3, and poly-ADP ribose polymerase (PARP) was performed. Quantitative real-time polymerase chain reaction (qPCR) was used to measure relative mRNA expression.
Treatment with resveratrol resulted in growth suppression and an increase in the cleavage of caspase-3 and PARP. A dose-dependent inhibition of ASCL1, a neuroedocrine transcription factor, was observed at the protein and mRNA levels. Protein levels of CgA, a marker of hormone secretion, were also reduced after treatment with resveratrol. A dose-dependent induction of Notch2 mRNA was observed by qPCR.
Resveratrol suppresses in vitro growth, likely through apoptosis, as demonstrated by cleavage of caspase-3 and PARP. Furthermore, resveratrol decreased neuroedocrine markers ASCL1 and chromogranin A. Induction of Notch2 mRNA suggests that this pathway may be central in the anti-MTC effects observed.
KeywordsResveratrol Medullary Thyroid Cancer Western Blot Testing Parafollicular Cell Notch2 mRNA
Supported in part by Department of Surgery T35 Short Term Training Grant (DK 062709-0401 to M.T.), Howard Hughes Medical Institute (to M.R.C.), National Institutes of Health (Grants RO1 CA121115 and RO1 CA109053 to H.C.), and American College of Surgeons George H. A. Clowes Jr. Memorial Research Career Development Award (to H.C.), and Carcinoid Cancer Foundation Research Award (to H.C.).
Conflicts of interest
The authors declare no conflict of interest.
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