Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis
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Jichang Wang2,3,*, Guangyue Li7,*, Yaochun Wang1, Shouching Tang5,6, Xin Sun4, Xuefei Feng1, Yan Li3, Gang Bao2, Pingping Li1, Xiaona Mao1, Maode Wang2, Peijun Liu1
1Center for Translational Medicine, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
2Department of Neurosurgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
3Department of Vascular Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
4Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China
5Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia, 30912, United States of America
6Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
7Department of Science and Technology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China
*These authors have contributed equally to this work
Peijun Liu, e-mail: email@example.com
Maode Wang, e-mail: firstname.lastname@example.org
Keywords: metformin, anti-angiogenesis, HER2, heregulin-β1, HIF-1α-VEGF signaling
Received: July 17, 2015 Accepted: October 23, 2015 Published: November 02, 2015
Anti-angiogenesis is currently considered as one of the major antitumor strategies for its protective effects against tumor emergency and later progression. The anti-diabetic drug metformin has been demonstrated to significantly inhibit tumor angiogenesis based on recent studies. However, the mechanism underlying this anti-angiogenic effect still remains an enigma. In this study, we investigated metformin-induced inhibitory effect on tumor angiogenesis in vitro and in vivo. Metformin pretreatment significantly suppressed tumor paracrine signaling-induced angiogenic promotion even in the presence of heregulin (HRG)-β1 (a co-activator of HER2) pretreatment of HER2+ tumor cells. Similar to that of AG825, a specific inhibitor of HER2 phosphorylation, metformin treatment decreased both total and phosphorylation (Tyr 1221/1222) levels of HER2 protein and significantly reduced microvessel density and the amount of Fitc-conjugated Dextran leaking outside the vessel. Furthermore, our results of VEGF-neutralizing and -rescuing tests showed that metformin markedly abrogated HER2 signaling-induced tumor angiogenesis by inhibiting VEGF secretion. Inhibition of HIF-1α signaling by using RNAi or YC-1, a specific inhibitor of HIF-1α synthesis, both completely diminished mRNA level of VEGF and greatly inhibited endothelial cell proliferation promoted by HER2+ tumor cell-conditioned medium in both the absence and presence of HRG-β1 pretreatment. Importantly, metformin treatment decreased the number of HIF-1α nucleus positive cells in 4T1 tumors, accompanied by decreased microvessel density. Our data thus provides novel insight into the mechanism underlying the metformin-induced inhibition of tumor angiogenesis and indicates possibilities of HIF-1α-VEGF signaling axis in mediating HER2-induced tumor angiogenesis.
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