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The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway
- Source :
- International journal of oncology. 54(2)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
MMP2
Angiogenesis
Cell Survival
Angiogenesis Inhibitors
Breast Neoplasms
Biology
Glutarates
03 medical and health sciences
chemistry.chemical_compound
Cell Movement
Human Umbilical Vein Endothelial Cells
Humans
Protein kinase B
Cell Proliferation
Neovascularization, Pathologic
Kinase insert domain receptor
Vascular Endothelial Growth Factor Receptor-2
Isocitrate Dehydrogenase
Endothelial stem cell
Vascular endothelial growth factor
030104 developmental biology
Oncology
chemistry
Gene Expression Regulation
Focal Adhesion Protein-Tyrosine Kinases
Cancer cell
Cancer research
Ketoglutaric Acids
Matrix Metalloproteinase 2
Tumor Hypoxia
Signal transduction
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 17912423
- Volume :
- 54
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- International journal of oncology
- Accession number :
- edsair.doi.dedup.....2de66e120f1359e7208662aa3d0c9019