Research Papers:
Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation
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Abstract
Xianmin Mu1,*, Ting Zhao1,*, Che Xu1, Wei Shi4, Biao Geng1, Jiajia Shen2, Chen Zhang1, Jinshun Pan1, Jing Yang1, Shi Hu1, Yuanfang Lv1, Hao Wen2, Qiang You1,3
1Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
2Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, China
3Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
4Department 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: [email protected]
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.
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PII: 14485