Snail modulates cell metabolism in MDCK cells.
Snail modulates cell metabolism in MDCK cells.
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Snail 调节 MDCK 细胞的细胞代谢。
DOI：
10.1016/j.bbrc.2013.02.035
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Haraguchi M
中科院分区：
文献类型：
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作者：
Eida S;Hotokezaka Y;Katayama I;Ichikawa Y;Tashiro S;Sumi T;Sumi M;Nakamura T;Haraguchi M
Snail是E-钙粘蛋白基因转录的抑制因子，诱导上皮细胞向间质细胞转化，并参与肿瘤的进展。Snail还介导对由血清耗竭诱导的细胞死亡的抵抗。相比之下，我们观察到，蜗牛表达MDCK（MDCK/蜗牛）细胞进行细胞死亡率高于控制（MDCK/neo）细胞在低葡萄糖培养基。因此，我们研究snail表达是否影响MDCK细胞中的细胞代谢。虽然糖酵解在MDCK/蜗牛细胞中不受影响，但它们确实表现出降低的丙酮酸脱氢酶（PDH）活性，其控制丙酮酸进入三羧酸（TCA）循环。事实上，在MDCK/蜗牛细胞中，参与TCA循环的多种酶的活性降低，包括线粒体NADP+依赖性异柠檬酸脱氢酶（IDH 2）、琥珀酸脱氢酶（SDH）和电子传递复合物II和复合物IV。因此，与MDCK/neo细胞相比，在MDCK/snail细胞中也观察到较低的ATP含量、较低的耗氧量和在缺氧条件下增加的存活率。此外，磷酸化和抑制PDH活性的丙酮酸脱氢酶激酶1（PDK 1）的表达和启动子活性在MDCK/snail细胞中增加，而参与脂肪胺分解和脂肪酸合成的丙氨酸氨基转移酶2（GLS 2）和ATP-柠檬酸裂解酶（ACLY）的表达水平在MDCK/snail细胞中降低。这些结果表明蜗牛通过改变关键酶的表达和活性来调节细胞代谢。这导致葡萄糖依赖性增强，并导致低葡萄糖条件下的细胞死亡。另一方面，对来自周围环境的氧气和营养物质的需求减少，可能赋予对缺氧和营养不良诱导的细胞死亡的抵抗力。
Snail, a repressor of E-cadherin gene transcription, induces epithelial-to-mesenchymal transition and is involved in tumor progression. Snail also mediates resistance to cell death induced by serum depletion. By contrast, we observed that snail-expressing MDCK (MDCK/snail) cells undergo cell death at a higher rate than control (MDCK/neo) cells in low-glucose medium. Therefore, we investigated whether snail expression influences cell metabolism in MDCK cells. Although gylcolysis was not affected in MDCK/snail cells, they did exhibit reduced pyruvate dehydrogenase (PDH) activity, which controls pyruvate entry into the tricarboxylic acid (TCA) cycle. Indeed, the activity of multiple enzymes involved in the TCA cycle was decreased in MDCK/snail cells, including that of mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2), succinate dehydrogenase (SDH), and electron transport Complex II and Complex IV. Consequently, lower ATP content, lower oxygen consumption and increased survival under hypoxic conditions was also observed in MDCK/snail cells compared to MDCK/neo cells. In addition, the expression and promoter activity of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the activity of PDH, was increased in MDCK/snail cells, while expression levels of glutaminase 2 (GLS2) and ATP-citrate lyase (ACLY), which are involved in glutaminolysis and fatty acid synthesis, were decreased in MDCK/snail cells. These results suggest that snail modulates cell metabolism by altering the expression and activity of key enzymes. This results in enhanced glucose dependency and leads to cell death under low-glucose conditions. On the other hand, the reduced requirements for oxygen and nutrients from the surrounding environment, might confer the resistance to cell death induced by hypoxia and malnutrition.