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

50 Citations (Scopus)

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

Fingerprint

Metformin
Vascular Endothelial Growth Factor A
Neoplasms
Neuregulin-1
Microvessels
Phosphorylation
Paracrine Communication
Conditioned Culture Medium
RNA Interference
Dextrans
Cell Nucleus
Emergencies
Endothelial Cells
Cell Proliferation
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis. / Wang, Jichang; Li, Guangyue; Wang, Yaochun; Tang, Shou-Ching; Sun, Xin; Feng, Xuefei; Li, Yan; Bao, Gang; Li, Pingping; Mao, Xiaona; Wang, Maode; Liu, Peijun.

In: Oncotarget, Vol. 6, No. 42, 01.01.2015, p. 44579-44592.

Research output: Contribution to journalArticle

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, vol. 6, no. 42, pp. 44579-44592. https://doi.org/10.18632/oncotarget.6373
Wang, Jichang ; Li, Guangyue ; Wang, Yaochun ; Tang, Shou-Ching ; Sun, Xin ; Feng, Xuefei ; Li, Yan ; Bao, Gang ; Li, Pingping ; Mao, Xiaona ; Wang, Maode ; Liu, Peijun. / Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis. In: Oncotarget. 2015 ; Vol. 6, No. 42. pp. 44579-44592.
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AU - Feng, Xuefei

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