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

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.

DOI: 10.18632/oncotarget.6373

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@article{Wang2015SuppressionOT, title={Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis.}, author={Jichang Wang and Guangyue Li and Yaochun Wang and Shouching Tang and Xin Sun and Xuefei Feng and Yan Li and Gang Bao and Pingping Li and Xiaona Mao and Maode Wang and Peijun Liu}, journal={Oncotarget}, year={2015}, volume={6 42}, pages={44579-92} }