Elevated 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.