Research Papers:

GRP78 enhances the glutamine metabolism to support cell survival from glucose deficiency by modulating the β-catenin signaling

Zongwei Li, Yingying Wang, Haili Wu, Lichao Zhang, Peng Yang and Zhuoyu Li _

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Oncotarget. 2014; 5:5369-5380. https://doi.org/10.18632/oncotarget.2105

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Zongwei Li1, Yingying Wang1, Haili Wu1, Lichao Zhang1, Peng Yang1 and Zhuoyu Li1,2

1 Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China

2 College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China


Zhuoyu Li, email:

Keywords: GRP78, β-catenin, adenomatous polyposis coli, glucose metabolism, glutamine metabolism

Received: April 20, 2014 Accepted: June 12, 2014 Published: June 14, 2014


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.

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