title: Biphasic effects of luteolin on interleukin-1β-induced cyclooxygenase-2 expression in glioblastoma cells.
abstract: Success in developing therapeutic approaches to target brain tumor-associated inflammation in patients has been limited. Given that the inflammatory microenvironment is a hallmark signature of solid tumor development, anti-inflammatory targeting strategies have been envisioned as preventing glioblastoma initiation or progression. Consumption of foods from plant origin is associated with reduced risk of developing cancers, a chemopreventive effect that is, in part, attributed to their high content of phytochemicals with potent anti-inflammatory properties. We explored whether luteolin, a common flavonoid in many types of plants, may inhibit interleukin (IL)-1β function induction of the inflammation biomarker cyclooxygenase (COX)-2. We found that IL-1β triggered COX-2 expression in U-87 glioblastoma cells and synergized with luteolin to potentiate or inhibit that induction in a biphasic manner. Luteolin pretreatment of cells inhibited IL-1β-mediated phosphorylation of inhibitor of κB, nuclear transcription factor-κB (NF-κB) p65, extracellular signal-regulated kinase-1/2, and c-Jun amino-terminal kinase in a concentration-dependent manner. Luteolin also inhibited AKT phosphorylation and survivin expression, while it triggered both caspase-3 cleavage and expression of glucose-regulated protein 78. These effects were all potentiated by IL-1β, in part through increased nuclear translocation of NF-κB p65. Finally, luteolin was able to reduce IL-1 receptor gene expression, and treatment with IL-1 receptor antagonist or gene silencing of IL-1 receptor prevented IL-1β/luteolin-induced COX-2 expression. Our results document a novel adaptive cellular response to luteolin, which triggers anti-survival and anti-inflammatory mechanisms that contribute to the chemopreventive properties of this diet-derived molecule.
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada. Electronic address: lamy.sylvie@uqam.ca.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lamy
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada. Electronic address: moldovan.paula_liana@courrier.uqam.ca.
authors.forename: Paula Liana
authors.initials: PL
authors.lastname: Moldovan
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada. Electronic address: ben_saad.aroua@courrier.uqam.ca.
authors.forename: Aroua
authors.initials: A
authors.lastname: Ben Saad
authors.affiliation: Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montréal, Québec H3C 3P8, Canada. Electronic address: annabi.borhane@uqam.ca.
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D047311:Luteolin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; D047311:Luteolin
keywords: COX-2; Glioblastoma; Inflammation; Interleukin-1; Luteolin; NF-κB