Oncometabolite succinate to promote angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation.

e23000 Background: 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 has 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. Methods: Succinate levels were measured in gastric cancer and paracancerous tissues as well as cell culture supernatants from normal cells and gastric cancer cells. Chemotactic motility, capillary structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) were determined in the presence of succinate in vitro. Moreover, the vessel formation in zebrafish embryo was also used to examine the effect of succinate on angiogenesis. The activation of STAT3 and ERK signaling by succinate was checked by Western Blot. Results: 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 pHUVECs in vitro, as well as promote 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. Conclusions: 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.