Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF-1α-induced pro-angiogenic factor

Abstract

Substantial data from preclinical studies have revealed the biphasic effects of statins on cardiovascular angiogenesis. Although some have reported the anti-angiogenic potential of statins in malignant tumors, however, the underlying mechanism remains poorly understood. The aim of this study is to elucidate the mechanism by which simvastatin, a member of the statin family, inhibits tumor angiogenesis. Simvastatin significantly suppressed tumor cells-conditioned medium (TCM)-induced angiogenic promotion in vitro, and resulted in a dose-dependent anti-angiogenesis in vivo. Further genetic silencing of HIF-1α reduced VEGF and FGF-2 expressions in 4T1 cells and correspondingly ameliorated HUVECs proliferation facilitated by TCM. Additionally, simvastatin induced angiogenic inhibition via a mechanism of post-transcriptional down-regulation of HIF-1α by increasing phosphorylation level of AMP kinase (AMPK). These results were further validated by the fact that AICAR reduced HIF-1α protein level and ameliorated the angiogenic ability of endothelial cells in vitro and in vivo. Critically, inhibition of AMPK phosphorylation by compound C almost completely abrogated simvastatin-induced anti-angiogenesis, which was accompanied by the reduction of protein levels of HIF-1α and its downstream pro-angiogenic factors. These findings demonstrate the mechanism in which simvastatin induces tumor anti-angiogenesis, and therefore identify the target that explains the beneficial effects of statins on malignant tumors.

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