Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.
Neurofilament heavy polypeptide regulates the Akt-beta-catenin pathway in human esophageal squamous cell carcinoma.
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DOI：
10.1371/journal.pone.0009003
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发表时间：
2010-02-03
期刊：
影响因子：
3.7
通讯作者：
Sidransky D
中科院分区：
文献类型：
--
作者：
Kim MS;Chang X;LeBron C;Nagpal JK;Lee J;Huang Y;Yamashita K;Trink B;Ratovitski EA;Sidransky D
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。我们观察到启动子甲基化和神经丝重多肽（NEFH）的表达丢失在一个显着比例的原发性食管鳞状细胞癌（ESCC）的样本是一个高肿瘤级别和先进的阶段。RNA干扰介导的NEFH基因敲低可促进食管鳞癌细胞在培养中的生长，并增加体内致瘤性，而NEFH的强制表达可显著抑制细胞生长和集落形成。NEFH的缺失通过激活Akt/β-catenin途径引起丙酮酸激酶-M2型上调和丙酮酸脱氢酶下调，导致有氧糖酵解增强和线粒体功能障碍。NEFH敲除细胞中糖酵解和线粒体功能障碍的加速在β-连环蛋白表达缺失的情况下受到抑制，并且通过糖酵解抑制剂2-脱氧葡萄糖或Akt抑制剂API-2的处理而降低。NEFH的缺失激活Akt/β-catenin途径并增加糖酵解和线粒体功能障碍。具有甲基化NEFH的癌细胞可以被靶向用于用解除调节的下游途径的特异性抑制剂破坏。
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/β-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 β-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/β-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.
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DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
影响因子：
8
作者：
Clement, G.;Braunschweig, R.;Benhattar, J.
通讯作者：
Benhattar, J.
影响因子：
21.3
作者：
Kawauchi, Keiko;Araki, Keigo;Tanaka, Nobuyuki
通讯作者：
Tanaka, Nobuyuki
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
8
作者：
Kim, M. S.;Chang, X.;Sidransky, D.
通讯作者：
Sidransky, D.