Impairment of tumor-initiating stem-like property and reversal of epithelial–mesenchymal transdifferentiation in head and neck cancer by resveratrol treatment
Article first published online: 13 JUN 2012
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Volume 56, Issue 8, pages 1247–1258, August 2012
How to Cite
Hu, F.-W., Tsai, L.-L., Yu, C.-H., Chen, P.-N., Chou, M.-Y. and Yu, C.-C. (2012), Impairment of tumor-initiating stem-like property and reversal of epithelial–mesenchymal transdifferentiation in head and neck cancer by resveratrol treatment. Mol. Nutr. Food Res., 56: 1247–1258. doi: 10.1002/mnfr.201200150
- Issue published online: 10 AUG 2012
- Article first published online: 13 JUN 2012
- Manuscript Accepted: 27 APR 2012
- Manuscript Revised: 23 APR 2012
- Manuscript Received: 14 MAR 2012
- Cancer Stem Cells;
- Epithelial-mesenchymal transition;
- Head and neck cancer;
- Tumor-initiating cells
Recent reports have demonstrated that head and neck cancer-derived tumor-initiating cells (HNC-TICs) presented high tumorigenic, chemoradioresistant, metastatic properties, and were coupled with gain of epithelial–mesenchymal transition (EMT) characteristics. The aim of this study was to investigate the chemotherapeutic effect and regulatory mechanisms of resveratrol on HNC-TICs.
Methods and results
We first observed that the treatment of resveratrol significantly downregulated the ALDH1 activity and CD44 positivity of head and neck cancer (HNC) cells in a dose-dependent manner (p < 0.05). Moreover, resveratrol treatment reduced self-renewal property and stemness genes signatures (Oct4, Nanog, and Nestin) expression in sphere-forming HNC-TICs. Additionally, the repressive effect of resveratrol on in vitro malignant properties including invasiveness/anchorage-independent growth was mediated by regulating productions of EMT markers Slug, ZEB1, N-cadherin, E-cadherin, and Vimentin. Importantly, an in vivo nude mice model showed that resveratrol treatment to xenograft tumors by oral gavage reduced tumor growth, stemness, and EMT markers in vivo. Lastly, synergistic effect of resveratrol and conventional chemotreatment attenuated tumor-initiating cells property in HNC-TICs.
Our results demonstrated that resveratrol would be a valuable therapeutics clinically in combination with conventional chemotherapy treatment modalities for malignant HNCs by elimination of tumor-initiating stem-like and EMT properties.