Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis
Lactate Dehydrogenase B Is Critical for Hyperactive mTOR-Mediated Tumorigenesis
复制标题
乳酸脱氢酶 B 对于高度活跃的 mTOR 介导的肿瘤发生至关重要。
DOI：
10.1158/0008-5472.can-10-1668
复制
发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Zha, Xiaojun;Wang, Fang;Zhang, Hongbing
哺乳动物雷帕霉素靶蛋白（mTOR）是受体酪氨酸激酶（RTK）-磷酸肌醇3-激酶（PI 3 K）-v-akt小鼠胸腺瘤病毒癌基因同源物1（AKT）信号传导途径的主要下游效应物。尽管这种信号网络在癌症中经常改变，但由于激活的mTOR而导致肿瘤发生的潜在机制在很大程度上仍然未知。我们在此报告，乳酸脱氢酶B（LDHB），一种糖酵解的关键酶激活剂，在TSC 1（-/-），TSC 2（-/-），PTEN（-/-）或激活的表达AKT 1的小鼠胚胎成纤维细胞（MEF）中以mTOR依赖的方式上调。LDHB基因表达被信号转导子和转录激活子3（STAT 3）反式激活，STAT 3是许多癌症中的关键致瘤驱动因子，在小鼠MEF和人癌细胞中充当下游mTOR效应子。LDHB减毒减弱了裸鼠中致癌TSC 2-null细胞的致瘤潜力。我们得出结论，LDHB是mTOR的下游靶点，对致癌mTOR介导的肿瘤发生至关重要。我们的研究结果为靶向LDHB作为由RTK-PI 3 K-AKT-mTOR信号级联的异常激活驱动的癌症的治疗策略提供了概念证明。
Mammalian target of rapamycin (mTOR) is a major downstream effector of the receptor tyrosine kinase (RTK)-phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homologue 1 (AKT) signaling pathway. Although this signaling network is frequently altered in cancer, the underlying mechanisms that cause tumorigenesis as a result of activated mTOR remain largely unknown. We report here that expression of lactate dehydrogenase B (LDHB), a critical enzymatic activator of glycolysis, was upregulated in an mTOR-dependent manner in TSC1(-/-), TSC2(-/-), PTEN(-/-), or activated AKT1-expressing mouse embryonic fibroblasts (MEF). LDHB gene expression was transactivated by signal transducer and activator of transcription 3 (STAT3), a key tumorigenic driver in many cancers, acting as a downstream mTOR effector in both mouse MEFs and human cancer cells. LDHB attenuation blunted the tumorigenic potential of oncogenic TSC2-null cells in nude mice. We concluded that LDHB is a downstream target of mTOR that is critical for oncogenic mTOR-mediated tumorigenesis. Our findings offer proof of concept for targeting LDHB as a therapeutic strategy in cancers driven by aberrant activation of the RTK-PI3K-AKT-mTOR signaling cascade.