Resveratrol Impedes the Stemness, Epithelial-Mesenchymal Transition, and Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma through p53 Activation

Yao-An Shen,Yau-Huei Wei,Yann-Jang Chen,Yi-Tao Hsieh,Chia-Yu Wang,Wei-Hsin Chi,Chien-Hung Lin

doi:10.1155/2013/590393

Abstract

Cancer stem cells (CSCs) are able to self-renew and are refractory to cancer treatment. To investigate the effects of resveratrol on CSCs of nasopharyngeal carcinoma (NPC), we employed a behavior selection strategy to isolate CSCs based on radioresistance, chemoresistance, and tumor sphere formation ability. These NPC CSCs displayed stem cell properties and underwent metabolic shift to predominately rely on glycolysis for energy supply. Intriguingly, we found that resveratrol turned off the metabolic switch, increased the reactive oxygen species (ROS) level, and depolarized mitochondrial membranes. These alterations in metabolism occurred concomitantly with the suppression of CSC properties including resistance to therapy, self-renewal capacity, tumor initiation capacity, and metastatic potential in NPC CSCs. We found that resveratrol impeded CSC properties through the activation of p53 and this effect could be reversed by knockdown of p53. Furthermore, resveratrol suppressed the stemness and EMT through reactivating p53 and inducing miR-145 and miR-200c, which were downregulated in NPC CSCs. In conclusion, we demonstrated that resveratrol employed the p53 pathway in regulating stemness, EMT, and metabolic reprogramming. Further investigation of the molecular mechanism of p53 activation by resveratrol may provide useful information for the development of novel therapies for cancer treatment through targeting to CSCs.

Highlights

Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer with high prevalence rates in Southeast China and Taiwan
The O2 consumption rates driven by ADP and succinate were lower in cancer stem cells (CSCs) compared with those in parental NPC cells (Figure 2(e)), which implied that these CSCs might not rely on mitochondrial respiration to produce energy
The level of prooxidants was relatively lower in CSCs compared with parental NPC cells through analysis of intracellular H2O2 with H2DCFH-DA (Figure 2(g))

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer with high prevalence rates in Southeast China and Taiwan. Unlike other head and neck cancers, most cases of NPC have high tendency to invade surrounding tissues and metastasize to regional lymph nodes at an early stage. Most mortality of NPC patients is due to local recurrence and distant metastases [1]. Chemotherapy and radiotherapy can improve survival rate, the prognosis remains poor for patients with relapse or metastatic diseases [2]. In order to effectively identify the target of therapy, the underlying mechanisms that lead to NPC recurrence and metastasis must be clarified. Thereby, the discovery of potential drugs targeting at CSCs may solve the clinical curative difficulties such as therapeutic resistance, recurrence, and metastasis

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Conclusion