Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

// Xianmin Mu 1, * , Ting Zhao 1, * , Che Xu 1 , Wei Shi 4 , Biao Geng 1 , Jiajia Shen 2 , Chen Zhang 1 , Jinshun Pan 1 , Jing Yang 1 , Shi Hu 1 , Yuanfang Lv 1 , Hao Wen 2 , Qiang You 1, 3 1 Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China 2 Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China 3 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, China 4 Department of Drug Screening and Evaluation, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu 210023, China * These authors have contributed equally to this work Correspondence to: Qiang You, email: Qiang.You@njmu.edu.cn Keywords: succinate, GPR91, gastric cancer, angiogenesis, ERK1/2 Received: October 20, 2016     Accepted: December 23, 2016     Published: January 04, 2017 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.