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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, 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 cell‐conditioned medium‐induced angiogenic promotion in vitro, and resulted in dose‐dependent anti‐angiogenesis in vivo. Further genetic silencing of hypoxia‐inducible factor‐1α ( HIF ‐1α) reduced vascular endothelial growth factor and fibroblast growth factor‐2 expressions in 4T1 cells and correspondingly ameliorated  HUVEC  proliferation facilitated by tumor cell‐conditioned medium. Additionally, simvastatin induced angiogenic inhibition through a mechanism of post‐transcriptional downregulation of  HIF ‐1α by increasing the phosphorylation level of  AMP  kinase. These results were further validated by the fact that 5‐aminoimidazole‐4‐carboxamide ribonucleotide reduced  HIF ‐1α protein levels 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 reveal the mechanism by which simvastatin induces tumor anti‐angiogenesis, and therefore identifies the target that explains the beneficial effects of statins on malignant tumors.

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