Journal
CANCER SCIENCE
Volume 109, Issue 5, Pages 1627-1637Publisher
WILEY
DOI: 10.1111/cas.13570
Keywords
AMPK; anti-angiogenesis; HIF-1; simvastatin; statin
Categories
Funding
- National Natural Science Foundation of China [81272342, 81472747, 81602638, 81602502]
- Keypoint Research and Invention Program of Shaanxi Province [2017SF-017, 2016SF196]
- Nature Science Foundation of Shaanxi Province [2016JM8125]
- College Scientific Research Foundation of Xi'an Jiaotong University [xjj2016104]
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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-1 (HIF-1) 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-1 by increasing the phosphorylation level of AMP kinase. These results were further validated by the fact that 5-aminoimidazole-4-carboxamide ribonucleotide reduced HIF-1 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-1 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.
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