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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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Acknowledgment

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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Authors and Affiliations

  1. Department of Surgery, Endocrine Research Laboratory, University of Wisconsin, Madison, WI, USA

    Matthew Truong BA, Mackenzie R. Cook MD, Scott N. Pinchot MD, Muthusamy Kunnimalaiyaan PhD & Herbert Chen MD, FACS

  2. University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Matthew Truong BA, Mackenzie R. Cook MD, Scott N. Pinchot MD, Muthusamy Kunnimalaiyaan PhD & Herbert Chen MD, FACS

  3. H4/722 Clinical Science Center, University of Wisconsin, Madison, WI, USA

    Herbert Chen MD, FACS

Authors
  1. Matthew Truong BA
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  2. Mackenzie R. Cook MD
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  3. Scott N. Pinchot MD
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  4. Muthusamy Kunnimalaiyaan PhD
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  5. Herbert Chen MD, FACS
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Corresponding author

Correspondence to Herbert Chen MD, FACS.

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Truong, M., Cook, M.R., Pinchot, S.N. et al. Resveratrol Induces Notch2-Mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer. Ann Surg Oncol 18, 1506–1511 (2011). https://doi.org/10.1245/s10434-010-1488-z

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  • DOI: https://doi.org/10.1245/s10434-010-1488-z

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