Abstract

BackgroundGreat progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined.MethodsGene expression pattern of NPC cells were used to test associations between Chibby and β-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, β-Catenin, and PDK1 by immunostaining.ResultsWe observed that Chibby, a β-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/β-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/β-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/β-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/β-Catenin signaling and PDK1.ConclusionsOur study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/β-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment.

Highlights

  • Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined

  • Our study reveals an association between Chibby expression and aerobic glycolysis in cancer, which highlights the importance of the Wnt/β-catenin pathway in regulating energy metabolism in nasopharyngeal carcinoma

  • Chibby has an inverse expression pattern with β-catenin and inhibits proliferation in nasopharyngeal carcinoma cell lines To determine whether Chibby is involved in the carcinogenesis of nasopharyngeal carcinoma, we analyzed the expression of Chibby in diverse nasopharyngeal carcinoma cell lines

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Summary

Introduction

Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. One of the most important hallmarks of cancer is aerobic glycolysis or the so-called Warburg effect. The Warburg effect was first described by Warburg over 90 years ago and states that cancer cells heavily rely on glycolysis for energy metabolism even under normal oxygen concentrations [1]. Unlike most normal cells, cancer cells derive a substantial amount of their energy from aerobic glycolysis, converting most incoming glucose to lactate rather than metabolizing it in the mitochondria through oxidative phosphorylation [2, 3]. The Warburg effect has been documented in many cancers, the underlying mechanisms driving and regulating aerobic glycolysis are not fully understood [4]. Uncovering the mechanisms underlying aerobic glycolysis in cancer cells could be helpful for the development of new therapeutic targets of human cancers [5]

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