title: Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice.
abstract: Cigarette smoking (CS) is a leading cause of death worldwide. The aryl hydrocarbon receptor (AHR) is partially responsible for tobacco-induced carcinogenesis although the underlying mechanisms involving early effector genes have yet to be determined. Here, we report that adrenomedullin (ADM) significantly contributes to the carcinogenicity of tobacco-activated AHR. CS and AHR activating ligands induced ADM in vitro and in vivo but not in AHR-deficient fibroblasts and mice. Ectopic transfection of AHR rescued ADM expression in AHR(-/-) fibroblasts whereas AHR blockage with siRNA in wild type cells significantly decreased ADM expression. AHR regulates ADM expression through two intronic xenobiotic response elements located close to the start codon in the ADM gene. Using tissue microarrays we showed that ADM and AHR were coupregulated in lung tumor biopsies from smoker patients. Microarray meta-analysis of 304 independent microarray experiments showed that ADM is elevated in smokers and smokers with cancer. In addition, ADM coassociated with a subset of AHR responsive genes and efficiently differentiated patients with lung cancer from nonsmokers. In a novel preclinical model of CS-induced tumor progression, host exposure to CS extracts significantly elevated tumor ADM although systemic treatment with the ADM antagonist NSC16311 efficiently blocked tobacco-induced tumor growth. In conclusion, ADM significantly contributes the carcinogenic effect of AHR and tobacco combustion products. We suggest that therapeutics targeting the AHR/ADM axis may be of clinical relevance in the treatment of tobacco-induced pulmonary malignancies.
authors.affiliation: Angiogenesis Core Facility, Radiation Oncology Branch, Radiation Oncology Branch, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 21702-1201, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Portal-Nuñez
authors.forename: Uma T
authors.initials: UT
authors.lastname: Shankavaram
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Nicole
authors.initials: N
authors.lastname: Datrice
authors.forename: Scott
authors.initials: S
authors.lastname: Atay
authors.forename: Marta
authors.initials: M
authors.lastname: Aparicio
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Camphausen
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Fernández-Salguero
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: Frank
authors.initials: F
authors.lastname: Cuttitta
authors.forename: Enrique
authors.initials: E
authors.lastname: Zudaire
mesh_terms: D000280:Administration, Inhalation; D053607:Adrenomedullin / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D014028:Tobacco Smoke Pollution; D053607:Adrenomedullin