Resveratrol induces Notch2-mediated apoptosis and suppression of neuroendocrine markers in medullary thyroid cancer

Ann Surg Oncol. 2011 May;18(5):1506-11. doi: 10.1245/s10434-010-1488-z. Epub 2010 Dec 24.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis / drug effects*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blotting, Western
  • Carcinoma, Medullary / drug therapy
  • Carcinoma, Medullary / metabolism
  • Carcinoma, Medullary / pathology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromogranin A / genetics
  • Chromogranin A / metabolism*
  • Humans
  • Neurosecretory Systems / drug effects
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA, Messenger / genetics
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / metabolism*
  • Resveratrol
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stilbenes / pharmacology*
  • Thyroid Neoplasms / drug therapy
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology*

Substances

  • ASCL1 protein, human
  • Antineoplastic Agents, Phytogenic
  • Basic Helix-Loop-Helix Transcription Factors
  • Chromogranin A
  • NOTCH2 protein, human
  • RNA, Messenger
  • Receptor, Notch2
  • Stilbenes
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Resveratrol