ZFIN ID: ZDB-PUB-170108-6
Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation
Mu, X., Zhao, T., Xu, C., Shi, W., Geng, B., Shen, J., Zhang, C., Pan, J., Yang, J., Hu, S., Lv, Y., Wen, H., You, Q.
Date: 2017
Source: Oncotarget   8(8): 13174-13185 (Journal)
Registered Authors: Zhao, Ting
Keywords: ERK1/2, GPR91, angiogenesis, gastric cancer, succinate
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Embryo, Nonmammalian/blood supply
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression/drug effects
  • Human Umbilical Vein Endothelial Cells/drug effects
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Human Umbilical Vein Endothelial Cells/physiology
  • Humans
  • Immunoblotting
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase 1/metabolism*
  • Mitogen-Activated Protein Kinase 3/metabolism*
  • Neovascularization, Physiologic/drug effects*
  • RNA Interference
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor/metabolism*
  • Stomach Neoplasms/metabolism
  • Stomach Neoplasms/pathology
  • Succinates/metabolism
  • Succinates/pharmacology*
  • Vascular Endothelial Growth Factor A/genetics
  • Vascular Endothelial Growth Factor A/metabolism*
  • Vascular Endothelial Growth Factor A/pharmacology
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 28061458 Full text @ Oncotarget
FIGURES
ABSTRACT
Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers have been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) in vitro, as well as promoting the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Taken together, these data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.
ADDITIONAL INFORMATION