Work

Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis

Year: 2015

Type: article

Abstract: // Jichang Wang 2, 3, * , Guangyue Li 7, * , Yaochun Wang 1 , Shouching Tang 5, 6 , Xin Sun 4 , Xuefei Feng 1 , Yan Li 3 , Gang Bao 2 , Pingping Li 1 , Xiaona Mao 1 , Maode Wang 2 , Peijun Liu 1 1 Center for Translational Medicine, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China 2 Department of Neurosurgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China 3 Department of Vascular Surgery, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, P.R.China 4 Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China 5 Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia, 30912, United States of America 6 Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China 7 Department 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 Correspondence to: Peijun Liu, e-mail: [email protected] Maode Wang, e-mail: [email protected] Keywords: metformin, anti-angiogenesis, HER2, heregulin-β1, HIF-1α-VEGF signaling Received: July 17, 2015 Accepted: October 23, 2015 Published: November 02, 2015 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.6373