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Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.

ABSTRACT: Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/beta-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of beta-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/beta-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.

SUBMITTER: Kim MS

PROVIDER: S-EPMC2815775 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.

Kim Myoung Sook MS Chang Xiaofei X LeBron Cynthia C Nagpal Jatin K JK Lee Juna J Huang Yiping Y Yamashita Keishi K Trink Barry B Ratovitski Edward A EA Sidransky David D

PloS one 20100203 2

Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH signifi ...[more]

PMID: 20140245

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Project description:BackgroundEsophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood.Materials and methodsEighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed.ResultsWe found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/β-catenin pathway. Specifically, apatinib induced the degradation of β-catenin and decreased its transcriptional activity through Akt/GSK-3β repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer.ConclusionOur study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/β-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.

Dataset Information

Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.

Publications

Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.

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