A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer.
A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer.
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作者：
高速率的有氧糖酵解是恶性转化的标志。越来越多的证据表明，不同的调节机制介导了广泛的癌症中出现的这种癌症相关的代谢变化。棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶（EML 4-ALK）融合蛋白见于约3-7%的非小细胞肺癌（NSCLC）。FDA批准的ALK抑制剂的分子证据和治疗效果表明EML 4-ALK是肺肿瘤发生的驱动因素。最近的一项临床研究表明，与EML 4-ALK阴性NSCLC相比，携带EML 4-ALK重排的NSCLC显示出更高的葡萄糖代谢。在目前的工作中，我们提供了EML 4-ALK与糖酵解途径限速酶之一己糖激酶II（HK 2）过表达相关的证据。EML 4-ALK与HK 2上调之间的联系对于EML 4-ALK重排的NSCLC细胞的高糖酵解率和增殖至关重要。我们鉴定了低氧诱导因子1α（HIF 1 α）作为在这些细胞中在常氧下驱动HK 2基因表达的关键转录因子。EML 4-ALK通过HIF 1 α mRNA的转录激活和PI 3 K-AKT途径诱导HIF 1 α蛋白的缺氧非依赖性但葡萄糖依赖性蓄积，以增强HIF 1 α蛋白的合成。EML 4-ALK介导的HIF 1 α、HK 2和糖酵解代谢上调在体内也高度活跃，这一点通过EML 4-ALK阳性NSCLC细胞生长的异种移植物的FDG-PET成像证明。我们的数据揭示了一种新的EML 4-ALK-HIF 1 α-HK 2级联反应，可增强EML 4-ALK阳性NSCLC的葡萄糖代谢。
A high rate of aerobic glycolysis is a hallmark of malignant transformation. Accumulating evidence suggests that diverse regulatory mechanisms mediate this cancer-associated metabolic change seen in a wide spectrum of cancer. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3-7% of non-small cell lung carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism compared to EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged NSCLC cells. We identified hypoxia-inducible factor 1α (HIF1α) as a key transcription factor to drive HK2 gene expression in normoxia in these cells. EML4-ALK induced hypoxia-independent but glucose-dependent accumulation of HIF1α protein via both transcriptional activation of HIF1α mRNA and the PI3K-AKT pathway to enhance HIF1α protein synthesis. The EML4-ALK-mediated upregulation of HIF1α, HK2 and glycolytic metabolism was also highly active in vivo as demonstrated by FDG-PET imaging of xenografts grown from EML4-ALK-positive NSCLC cells. Our data reveal a novel EML4-ALK-HIF1α-HK2 cascade to enhance glucose metabolism in EML4-ALK-positive NSCLC.
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影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
影响因子：
13.3
作者：
Ferreira, Joao Vasco;Fofo, Hugo;Pereira, Paulo
通讯作者：
Pereira, Paulo
影响因子：
4.8
作者：
Hubbi, Maimon E.;Hu, Hongxia;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
DOI：
10.2183/pjab.91.193
发表时间：
2015
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Mano H
通讯作者：
Mano H
影响因子：
8
作者：
Wu, J.;Mukherjee, A.;Lebman, D. A.;Fang, X.
通讯作者：
Fang, X.