Oncotarget

Research Papers:

Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation

Cristina Gallo, Katiuscia Dallaglio, Barbara Bassani, Teresa Rossi, Armando Rossello, Douglas M. Noonan, Gabriele D’Uva, Antonino Bruno and Adriana Albini _

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Oncotarget. 2016; 7:59917-59931. https://doi.org/10.18632/oncotarget.10990

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Abstract

Cristina Gallo1, Katiuscia Dallaglio1, Barbara Bassani2, Teresa Rossi1, Armando Rossello3, Douglas M. Noonan4, Gabriele D’Uva2, Antonino Bruno2, Adriana Albini2

1IRCCS “Istituto in Tecnologie Avanzate e Modelli Assistenziali in Oncologia” Arcispedale S. Maria Nuova, Reggio Emilia, Italy

2Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy

3Department of Pharmacy, Pisa University, Pisa, Italy

4Department of Biotechnologies and Life Sciencies, University of Insubria, Varese, Italy

Correspondence to:

Adriana Albini, email: albini.adriana@gmail.com

Keywords: angiogenesis, xanthohumol, AMPK, endothelial cells, polyphenols

Received: March 25, 2016    Accepted: June 06, 2016    Published: August 1, 2016

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.


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