title: Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration.
abstract: Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.
authors.affiliation: Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, Centre-ville, Montréal, Québec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Michaud-Levesque
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bousquet-Gagnon
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015850:Interleukin-6; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D019938:Cyclin D1; D011794:Quercetin; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D020778:Matrix Metalloproteinase 2