We previously revealed that
tumor cell-derived
angiopoietin-like protein 2 (ANGPTL2) accelerates the metastatic capacity of
tumors in an autocrine/paracrine manner by activating
tumor cell motility and invasiveness and the epithelial-mesenchymal transition. However, the effects of ANGPTL2 on
cancer cell glycolytic metabolism, which is a hallmark of
tumor cells, are unknown. Here we report evidence supporting a role for
tumor cell-derived ANGPTL2 in establishing a preference for glycolytic metabolism. We report that a highly metastatic
lung cancer cell subline expressing abundant ANGPTL2 showed upregulated expression of the
glucose transporter GLUT3 as well as enhanced glycolytic metabolism relative to a less metastatic parental line. Most notably, ANGPTL2 overexpression in the less metastatic line activated glycolytic metabolism by increasing GLUT3 expression. Moreover, ANGPTL2 signaling through
integrin α5β1 increased GLUT3 expression by increasing
transforming growth factor-β (TGF-β) signaling and expression of the downstream
transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Conversely, ANGPTL2 knockdown in the highly metastatic subline decreased TGF-β1, ZEB1, and GLUT3 expression and antagonized glycolytic metabolism. In primary
tumor cells from patients with
lung cancer, ANGPTL2 expression levels correlated with GLUT3 expression. Overall, this work suggests that
tumor cell-derived ANGPTL2 accelerates activities associated with glycolytic metabolism in
lung cancer cells by activating TGF-β-ZEB1-GLUT3 signaling.