Abstract
Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.
| Original language | English |
|---|---|
| Pages (from-to) | 59917-59931 |
| Number of pages | 15 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 37 |
| DOIs | |
| Publication status | Published - 2016 |
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Keywords
- AMPK
- Angiogenesis
- Endothelial cells
- Polyphenols
- Xanthohumol
ASJC Scopus subject areas
- Oncology
Cite this
Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation. / Gallo, Cristina; Dallaglio, Katiuscia; Bassani, Barbara; Rossi, Teresa; Rossello, Armando; Noonan, Douglas M; D'Uva, Gabriele; Bruno, Antonino; Albini, Adriana.
In: Oncotarget, Vol. 7, No. 37, 2016, p. 59917-59931.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation
AU - Gallo, Cristina
AU - Dallaglio, Katiuscia
AU - Bassani, Barbara
AU - Rossi, Teresa
AU - Rossello, Armando
AU - Noonan, Douglas M
AU - D'Uva, Gabriele
AU - Bruno, Antonino
AU - Albini, Adriana
PY - 2016
Y1 - 2016
N2 - Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.
AB - Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKβ, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.
KW - AMPK
KW - Angiogenesis
KW - Endothelial cells
KW - Polyphenols
KW - Xanthohumol
UR - http://www.scopus.com/inward/record.url?scp=84991320293&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84991320293&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10990
DO - 10.18632/oncotarget.10990
M3 - Article
VL - 7
SP - 59917
EP - 59931
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 37
ER -