title: Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide.
abstract: The interaction between epithelial and stromal cells through soluble factors such as cytokines plays an important role in carcinogenesis. Breaking this cancer-promoting interaction poses an opportunity for cancer prevention. The tumor-promoting function of interleukin 6 (IL-6) has been documented; however, the underlying mechanisms of this function in lung carcinogenesis are not well elucidated. Here, we show that benzo[a]pyrene diol epoxide (BPDE, the active metabolite of cigarette smoke carcinogen benzo[a]pyrene)-induced human bronchial epithelial cell (HBEC) transformation was enhanced by IL-6 in vitro. The carcinogen/IL-6-transformed cells exhibited higher expression of STAT3 (signal transducer and activator of transcription 3) when compared with cells transformed by BPDE alone. Constitutive STAT3 activation drove cell proliferation and survival through anti-apoptosis gene expression. We further show that quercetin, a dietary compound having preventive properties for lung cancer, decreased BPDE-stimulated IL-6 secretion from human lung fibroblasts through inhibition of the NF-κB and ERK pathways. The inhibition was accomplished at clinically achievable concentrations of the compound. Finally, quercetin blocked IL-6-induced STAT3 activation in HBECs, and IL-6 enhancement of HBEC transformation by BPDE was abolished by quercetin treatment. Altogether, our data reveal novel mechanisms for IL-6 in lung carcinogenesis and for the preventive role of quercetin in the process. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace -----Respiratory Research Institute, Albuquerque, New Mexico. wchen@lrri.org.
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace -----Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Mabel T
authors.initials: MT
authors.lastname: Padilla
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace -----Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Jacek
authors.initials: J
authors.lastname: Krzeminski
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace -----Respiratory Research Institute, Albuquerque, New Mexico. ylin@lrri.org.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000009:adverse effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D011794:Quercetin
keywords: NF-kappa B; STAT3 transcription factor; carcinogenesis; extracellular signal-regulated MAP kinases