食管癌细胞中PI3K/AKT-HIF1α36890;路对糖酵解的影响

项目名称： 食管癌细胞中PI3K/AKT-HIF1α36890;路对糖酵解的影响

项目编号： No.30800511

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 朱宏

作者单位： 南京医科大学

项目金额： 20万元

中文摘要： 糖酵解是肿瘤细胞获得能量的主要途径，在肿瘤中高表达的HIF-1α26159;调节糖酵解的重要蛋白。本研究通过对食管癌细胞HIF-1α12289;PI3K/AKT通路和糖酵解酶表达的调控，探讨食管癌细胞中糖酵解的调节机制。研究发现随着环境氧浓度降低，食管癌细胞Eca109、TE1、TE13中HIF-1α34507;白表达增加，糖酵解酶类表达增强、活性增加，细胞外液乳酸蓄积增加；siRNA分别抑制HIF-1α21644;AKT表达后，细胞内糖酵解酶表达减少，活性降低，乳酸浓度下降；分别采用EGF、wortmannin和succinate调控AKT和HIF1α36890;路，发现刺激或阻断AKT能够显著改变不同氧环境下食管癌细胞糖酵解酶表达及乳酸形成，而抑制HIF-1α38477;解亦能促进糖酵解酶的表达及糖酵解过程。研究提示，PI3K/AKT和HIF-1α36884;径均参与了食管癌细胞的糖酵解过程。正常氧分压下PI3K/AKT途径可通过HIF-1α20316;用糖酵解过程，但这一过程并非完全依赖于HIF-1α12290;而环境缺氧依赖于HIF-1α20419;进食管癌细胞糖酵解，这一过程与PI3K/AKT活化有关。针对PI3K/AKT-HIF-1α36884;径调控能够影响食管癌细胞糖酵解过程。

中文关键词： 食管肿瘤；细胞缺氧；糖酵解；能量代谢；蛋白激酶B

英文摘要： Glycolysis is the preferable method for many cancer cells to meet energy demands. The overexpression of HIF-1α65288;hypoxia inducible factor-1α65289;in tumor cells is important for glycolysis. To explore the mechanism of glycolysis in esophageal cancer, we regulated the expression level of HIF-1αKT and activity of PI3K/AKT pathway by siRNA or drugs to observe the expression of GLUT1,HKII,LDHA, PFK2 (enzymes related to glycolysis) and output of lactic acid. With environmental oxygen concentration dropping, we found the expression level of HIF-1αnd enzymes related to glycolysis increase in esophageal cancer cell Eca109, TE1 and TE13 cells. Meanwhile, the activity of glycolysis enzymes and concentration of lactic acid were increased; After downregulating the expression of HIF-1αnd AKT respectively by siRNA, the level of expression and activity of glycolysis enzymes is reduced, and concentration of extracellular lactic acid decreased; EGF, wortmannin and rapamycin were applied to activate or block the PI3K/AKT pathway, the expression of glycolysis enzymes and the concentration of lactic acid of esophageal cancer cells changed significantly in different oxygen environment, and inhibiting HIF-1αegradation by succinate also can promote glycolysis enzyme expression and glycolysis. Our findings suggest that PI3K/AKT and HIF-1αathway may be engaged in esophageal cancer cells glycolysis. PI3K/AKT pathway has an important role in the glycolysis of cancer cells through HIF-1 αnder normal oxygen pressures, but this process might be independent of HIF-1 α But in hypoxia environment, HIF-1 αlays a key role in promoting glycolysis of esophageal cancer cells, which is related to the function of PI3K/AKT pathway. Regulation of PI3K/AKT-HIF-1αathway can affect glycolysis process in esophageal cancer cells. This might be a new target for future therapy.

英文关键词： esophageal neoplasm; cell hypoxia; glycolysis; energy metabolism; Protein kinase B