Abstract
AbstractElevated rates of glycolysis in cancer cells support tumor growth, in a process that typically depends on oncogene-induced increases in the expression and/or activity of enzymes in the glycolytic pathway. The NEDD9 scaffolding protein is upregulated in many advanced tumors, with increased NEDD9 promoting the activity of SRC and other effectors that promote invasion and metastasis. We here define a new role for NEDD9 in support of glycolysis. NEDD9 knockdown significantly impaired glycolysis in multiple lung cancer cell lines This was accompanied by post-transcriptional downregulation of steady-state levels of hexokinases (HK1 and HK2), which catalyze early steps in the glycolytic cascade, key rate limiting enzyme phosphofructokinase (PFK1), and downstream glyceraldehyde phosphate dehydrogenase (GAPDH). In mice, protein levels of HK1, HK2, PFK1, and GAPDH were depressed in Krastm4Tyj/J/Trp53tm1Brn/J (KP) non-small cell lung tumors with null versus wild type Nedd9. Reciprocally, depletion of HK1 or HK2 elevated NEDD9 expression, as did the treatment of cells with 2-deoxyglucose (2DG), an inhibitor of glycolysis; whereas overexpression of hexokinases promoted NEDD9 dephosphorylation, associated with reduced NEDD9 activity. Together, these data for the first time suggest a negative feedback circuit involving NEDD9 and glycolytic enzymes that may contribute to NEDD9 action in promoting the aggressive growth of advanced tumors.
Funder
U.S. Department of Defense
U.S. Department of Health & Human Services | NIH | National Cancer Institute
William Wikoff Smith Charitable Trust
William J. Avery Postdoctoral Fellowship from Fox Chase Cancer Center
U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Molecular Biology
Cited by
8 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献