Open AccessThe oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway
Author(s) -
Jiyoon Seok,
SooHyun Yoon,
S. H. Lee,
Jong Hwa Jung,
You Mie Lee
Publication year - 2018
Publication title -
international journal of oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.405
H-Index - 122
ISSN - 1019-6439
DOI - 10.3892/ijo.2018.4649
Subject(s) - angiogenesis , biology , protein kinase b , vascular endothelial growth factor , cancer research , kinase insert domain receptor , vascular endothelial growth factor a , microbiology and biotechnology , signal transduction , vegf receptors
The mutation of isocitrate dehydrogenase (IDH)1 (R132H) and IDH2 (R172K) and the induction of hypoxia in various solid tumors results in alterations in metabolic profiles, including the production of the d‑ or l‑forms of 2‑hydroxyglutarate (2HG) from α‑ketoglutarate in aerobic metabolism in the tricarboxylic acid (TCA) cycle. However, it is unclear whether the oncometabolite d‑2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d‑2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. The results revealed that treatment with d‑2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration‑dependent manner. Wound healing and cell migration (examined by Transwell assay) were significantly increased by d‑2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d‑2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d‑2HG. d‑2HG activated VEGF receptor (VEGFR)2 and VEGFR2 downstream signaling, extracellular signal‑regulated kinase 1/2, focal adhesion kinase, AKT and matrix metalloproteinase (MMP)2. Taken together, the findings of this study suggested that d‑2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity.