Head and Neck Cancer Research Division, Department of Otolaryngology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2010 Feb 3;5(2):e9003. doi: 10.1371/journal.pone.0009003.
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.
有氧糖酵解和线粒体功能障碍是侵袭性癌症生长的共同特征。我们观察到神经丝重链多肽（NEFH）在相当一部分高肿瘤分级和晚期原发性食管鳞状细胞癌（ESCC）样本中存在启动子甲基化和表达缺失。RNA 干扰介导的 NEFH 敲低加速了 ESCC 细胞在培养中的生长，并增加了体内的致瘤性，而 NEFH 的强制表达则显著抑制了细胞生长和集落形成。NEFH 的缺失导致丙酮酸激酶-M2 型的上调和丙酮酸脱氢酶的下调，通过激活 Akt/β-catenin 通路，导致有氧糖酵解和线粒体功能障碍增强。在没有β-catenin 表达的情况下，NEFH 敲低细胞中的糖酵解加速和线粒体功能障碍被抑制，并且通过使用糖酵解抑制剂 2-脱氧葡萄糖或 Akt 抑制剂 API-2 处理而减少。NEFH 的缺失激活 Akt/β-catenin 通路并增加糖酵解和线粒体功能障碍。可以用针对失调下游途径的特异性抑制剂靶向破坏甲基化的 NEFH 癌细胞。
