Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

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...

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Published in:Cancer science 2020-04, Vol.111 (4), p.1241-1253
Main Authors: Osumi, Hironobu, Horiguchi, Haruki, Kadomatsu, Tsuyoshi, Tashiro, Kyosei, Morinaga, Jun, Takahashi, Takashi, Ikeda, Koei, Ito, Takaaki, Suzuki, Makoto, Endo, Motoyoshi, Oike, Yuichi
Format: Article
Language:English
Subjects:
Angiopoietin
Angiopoietin-like Proteins - genetics
ANGPTL2
Autocrine Communication - genetics
Autocrine signalling
Biotechnology
cancer metabolism
Cell Line, Tumor
Cell Movement - genetics
Cell Proliferation - genetics
Dehydrogenases
Epithelial-Mesenchymal Transition - genetics
Female
Gene Expression Regulation, Neoplastic - genetics
Glucose
Glucose transporter
Glucose Transporter Type 3 - genetics
GLUT3
Glycolysis
Glycolysis - genetics
Homeobox
Humans
Integrin alpha5beta1 - genetics
Invasiveness
Kinases
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
Mesenchyme
Metabolism
Metastases
Metastasis
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
Neoplasm Metastasis
Original
Paracrine Communication - genetics
Paracrine signalling
Proteins
Software
Thoracic surgery
Transforming Growth Factor beta - genetics
Transforming growth factor-b
Transforming growth factor-b1
Tumor cells
Tumors
ZEB1
Zinc Finger E-box-Binding Homeobox 1 - genetics
Zinc finger proteins
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Summary: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. Tumor cell‐derived angiopoietin‐like protein 2 (ANGPTL2) accelerates metastatic capacity of tumors in an autocrine/paracrine manner by activating tumor cell motility and invasiveness and epithelial‐mesenchymal transition. Here we report evidence supporting a role for tumor cell‐derived ANGPTL2 in establishing a preference for glycolytic metabolism. 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.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14337