Li Zongwei, Wang Yingying, Wu Haili, Zhang Lichao, Yang Peng, Li Zhuoyu
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China.
Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China. College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China.
Oncotarget. 2014 Jul 30;5(14):5369-80. doi: 10.18632/oncotarget.2105.
To support the high rates of proliferation, cancer cells undergo the metabolic reprogramming: aerobic glycolysis and glutamine addiction. Though glucose regulated protein 78 (GRP78) is a glucose-sensing protein and frequently highly expressed in tumor cells, its roles in glucose and glutamine metabolic regulation remain poorly unknown. We report here that glucose deficiency-induced GRP78 enhances β-catenin signaling and consequently promotes its downstream c-Myc-mediated glutamine metabolism in colorectal cancer cells. Mechanistically, GRP78 elevates intracellular free β-catenin level via disruption of adenomatous polyposis coli (APC)-β-catenin and E-cadherin-β-catenin protein complexes. Notably, overexpression of GRP78 causes APC protein downregulation in proteasome- and lysosome-independent manners. Further mechanistic studies reveal that GRP78 facilitates the extracellular release of APC, thereby rendering the liberation of β-catenin from APC. Furthermore, GRP78 acts through both hindering E-cadherin expression and impairing the interaction of E-cadherin with β-catenin to indirectly and directly influence E-cadherin-β-catenin complex stability. Our study reveals that GRP78 is a novel molecular link between metabolic alterations and signal transduction during tumor progression.
为了支持高增殖率，癌细胞会进行代谢重编程：有氧糖酵解和谷氨酰胺成瘾。尽管葡萄糖调节蛋白78（GRP78）是一种葡萄糖感应蛋白，且在肿瘤细胞中经常高度表达，但其在葡萄糖和谷氨酰胺代谢调节中的作用仍鲜为人知。我们在此报告，葡萄糖缺乏诱导的GRP78增强β-连环蛋白信号传导，从而促进其下游c-Myc介导的结肠癌细胞谷氨酰胺代谢。机制上，GRP78通过破坏腺瘤性息肉病蛋白（APC）-β-连环蛋白和E-钙黏蛋白-β-连环蛋白蛋白复合物来提高细胞内游离β-连环蛋白水平。值得注意的是，GRP78的过表达以不依赖蛋白酶体和溶酶体的方式导致APC蛋白下调。进一步的机制研究表明，GRP78促进APC的细胞外释放，从而使β-连环蛋白从APC中释放出来。此外，GRP78通过阻碍E-钙黏蛋白表达和损害E-钙黏蛋白与β-连环蛋白的相互作用，间接和直接影响E-钙黏蛋白-β-连环蛋白复合物的稳定性。我们的研究表明，GRP78是肿瘤进展过程中代谢改变与信号转导之间的一种新型分子联系。
