Wnt信號通路在胚胎發(fā)育中發(fā)揮重要作用，而它的失調(diào)可導(dǎo)致多種惡性腫瘤,。Wnt信號通路可介導(dǎo)Snail依賴的上皮-間葉組織轉(zhuǎn)變（EMT）。而EMT可導(dǎo)致腫瘤的侵襲和轉(zhuǎn)移。5月25日Cancer Research 雜志在線發(fā)表了Su Yeon Lee等人的研究論文揭示了Wnt/Snail腫瘤發(fā)生和發(fā)展中的新功能。
研究證實,，Wnt通過抑制細(xì)胞色素氧化酶C（COX）的三個亞基：COXVIc, COXVIIa, 和 COXVIIc的表達(dá),，抑制線粒體呼吸及COX活力,。此外，Wnt還可通過增加葡萄糖的消耗和乳酸的生成,，并且誘導(dǎo)丙酮酸羧化酶來調(diào)節(jié)糖代謝向糖酵解的方向傾斜,。Wnt誘導(dǎo)線粒體抑制和糖酵解作用增加是通過經(jīng)典的β-catenin/T細(xì)胞因子4 (TCF4)/Snail途徑實現(xiàn)的。
這些研究發(fā)現(xiàn),，揭示了Wnt/Snail信號途徑在腫瘤生長和進(jìn)展過程中調(diào)節(jié)線粒體呼吸和糖代謝的新功能,。他們還進(jìn)一步證實短發(fā)卡RNA（shRNA）介導(dǎo)的EMT誘導(dǎo)因子E-cadherin下調(diào)，可抑制線粒體呼吸并通過激活Snail上調(diào)糖酵解作用,。這提示,，EMT可有助于Wnt/Snail對線粒體呼吸和糖代謝的調(diào)節(jié)。(生物谷.Bioon.com)
doi:10.1158/0008-5472.CAN-12-0006
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PMID:
Wnt/Snail Signaling Regulates Cytochrome C Oxidase and Glucose Metabolism
Su Yeon Lee,Hyun Min Jeon,Min Kyung Ju et al.
Abstract
Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. It induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we demonstrate that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. In addition, Wnt induces a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. Wnt-induced mitochondrial repression and glycolytic switch occur by the canonical β-catenin/T-cell factor 4 (TCF4)/Snail pathway. These findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. We further demonstrate that short hairpin RNA (shRNA)-mediated knockdown of E-cadherin, which can induce EMT, represses mitochondrial respiration and induces a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism.
