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

Jichang Wang, Guangyue Li, Yaochun Wang, Shou-Ching Tang, Xin Sun, Xuefei Feng, Yan Li, Gang Bao, Pingping Li, Xiaona Mao, Maode Wang, Peijun Liu

Research output: Contribution to journalArticle

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)44579-44592
Number of pages14
JournalOncotarget
Volume6
Issue number42
DOIs
StatePublished - Jan 1 2015

Keywords

  • Anti-angiogenesis
  • HER2
  • HIF-1α-VEGF signaling
  • Heregulin-β1
  • Metformin

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Wang, J., Li, G., Wang, Y., Tang, S-C., Sun, X., Feng, X., Li, Y., Bao, G., Li, P., Mao, X., Wang, M., & Liu, P. (2015). Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis. Oncotarget, 6(42), 44579-44592. https://doi.org/10.18632/oncotarget.6373