Resveratrol Induces Notch2-Mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer

Department of Surgery, University of Wisconsin, Madison, WI, USA.
Annals of Surgical Oncology (Impact Factor: 3.93). 12/2010; 18(5):1506-11. DOI: 10.1245/s10434-010-1488-z
Source: PubMed


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.

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    • "Contradictory results have previously been reported with regard to the inhibition of proliferation and induction of apoptosis by resveratrol. Certain studies have reported that resveratrol treatment induces apoptosis in various tumor cells (29–33). However, other studies have reported that resveratrol induces differentiation, but not apoptosis, in certain types of cancer cells (34–36). "
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    • "Cell proliferation was measured via 3-(4, 5-dimethylthiazol-2yl)-2, 5 diphenyltetrazolium bromide (MTT) assay as previously described 4,23. In brief, cells were plated in quadruplicates in 24-well plates under standard conditions. "
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    • "PTE may have greater biological activity due better bioavailability resulting from the substitution of a hydroxyl group with a methoxyl group, which increases the molecule’s lipophilicity [8]. Studies have also shown that resveratrol can induce the apoptosis of various types of cancer cells through the regulation of the Notch signaling pathway [9], [10]. However, the effects of PTE on human lung adenocarcinoma and the mechanisms responsible for these effects have not been elucidated. "
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