Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Ji‐Chang, Li, Xiong‐Xiong, Sun, Xin, Li, Guang‐Yue, Sun, Jing‐Lan, Ye, Yuan‐Peng, Cong, Long‐Long, Li, Wei‐Ming, Lu, Shao‐Ying, Feng, Jun, Liu, Pei‐Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980150/
https://www.ncbi.nlm.nih.gov/pubmed/29532562
http://dx.doi.org/10.1111/cas.13570
_version_ 1783327839000461312
author Wang, Ji‐Chang
Li, Xiong‐Xiong
Sun, Xin
Li, Guang‐Yue
Sun, Jing‐Lan
Ye, Yuan‐Peng
Cong, Long‐Long
Li, Wei‐Ming
Lu, Shao‐Ying
Feng, Jun
Liu, Pei‐Jun
author_facet Wang, Ji‐Chang
Li, Xiong‐Xiong
Sun, Xin
Li, Guang‐Yue
Sun, Jing‐Lan
Ye, Yuan‐Peng
Cong, Long‐Long
Li, Wei‐Ming
Lu, Shao‐Ying
Feng, Jun
Liu, Pei‐Jun
author_sort Wang, Ji‐Chang
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5980150
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-59801502018-06-06 Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor Wang, Ji‐Chang Li, Xiong‐Xiong Sun, Xin Li, Guang‐Yue Sun, Jing‐Lan Ye, Yuan‐Peng Cong, Long‐Long Li, Wei‐Ming Lu, Shao‐Ying Feng, Jun Liu, Pei‐Jun Cancer Sci Original Articles 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. John Wiley and Sons Inc. 2018-04-15 2018-05 /pmc/articles/PMC5980150/ /pubmed/29532562 http://dx.doi.org/10.1111/cas.13570 Text en © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Wang, Ji‐Chang
Li, Xiong‐Xiong
Sun, Xin
Li, Guang‐Yue
Sun, Jing‐Lan
Ye, Yuan‐Peng
Cong, Long‐Long
Li, Wei‐Ming
Lu, Shao‐Ying
Feng, Jun
Liu, Pei‐Jun
Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title_full Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title_fullStr Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title_full_unstemmed Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title_short Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor
title_sort activation of ampk by simvastatin inhibited breast tumor angiogenesis via impeding hif‐1α‐induced pro‐angiogenic factor
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980150/
https://www.ncbi.nlm.nih.gov/pubmed/29532562
http://dx.doi.org/10.1111/cas.13570
work_keys_str_mv AT wangjichang activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT lixiongxiong activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT sunxin activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT liguangyue activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT sunjinglan activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT yeyuanpeng activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT conglonglong activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT liweiming activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT lushaoying activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT fengjun activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor
AT liupeijun activationofampkbysimvastatininhibitedbreasttumorangiogenesisviaimpedinghif1ainducedproangiogenicfactor