title: Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation.
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.
authors: IRCCS "Istituto in Tecnologie Avanzate e Modelli Assistenziali in Oncologia" Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
authors: Cristina
authors: C
authors: Gallo
authors: IRCCS "Istituto in Tecnologie Avanzate e Modelli Assistenziali in Oncologia" Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
authors: Katiuscia
authors: K
authors: Dallaglio
authors: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors: Barbara
authors: B
authors: Bassani
authors: IRCCS "Istituto in Tecnologie Avanzate e Modelli Assistenziali in Oncologia" Arcispedale S. Maria Nuova, Reggio Emilia, Italy.
authors: Teresa
authors: T
authors: Rossi
authors: Department of Pharmacy, Pisa University, Pisa, Italy.
authors: Armando
authors: A
authors: Rossello
authors: Department of Biotechnologies and Life Sciencies, University of Insubria, Varese, Italy.
authors: Douglas M
authors: DM
authors: Noonan
authors: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors: Gabriele
authors: G
authors: D'Uva
authors: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors: Antonino
authors: A
authors: Bruno
authors: Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy.
authors: Adriana
authors: A
authors: Albini
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D027582:Humulus; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D054876:Prenylation; D011427:Propiophenones / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020533:Angiogenesis Inhibitors; D005419:Flavonoids; D011427:Propiophenones; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C104536:xanthohumol
keywords: AMPK; angiogenesis; endothelial cells; polyphenols; xanthohumol