Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice

Sergio Portal-Nunẽz, Uma T. Shankavaram, Mahadev Rao, Nicole Datrice, Scott Atay, Marta Aparicio, Kevin A. Camphausen, Pedro M. Fernández-Salguero, Han Chang, Pinpin Lin, David S. Schrump, Stavros Garantziotis, Frank Cuttitta, Enrique Zudaire

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 signi ficantly 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.

Original languageEnglish
Pages (from-to)5790-5800
Number of pages11
JournalCancer Research
Volume72
Issue number22
DOIs
Publication statusPublished - 15-11-2012

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Adrenomedullin
Aryl Hydrocarbon Receptors
Smoke
Tobacco Products
Tobacco
Smoking
Neoplasms
Fibroblasts
Genes
Lung
Initiator Codon
Response Elements
Xenobiotics
Microarray Analysis
Small Interfering RNA
Transfection
Meta-Analysis

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Portal-Nunẽz, S., Shankavaram, U. T., Rao, M., Datrice, N., Atay, S., Aparicio, M., ... Zudaire, E. (2012). Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice. Cancer Research, 72(22), 5790-5800. https://doi.org/10.1158/0008-5472.CAN-12-0818
Portal-Nunẽz, Sergio ; Shankavaram, Uma T. ; Rao, Mahadev ; Datrice, Nicole ; Atay, Scott ; Aparicio, Marta ; Camphausen, Kevin A. ; Fernández-Salguero, Pedro M. ; Chang, Han ; Lin, Pinpin ; Schrump, David S. ; Garantziotis, Stavros ; Cuttitta, Frank ; Zudaire, Enrique. / Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice. In: Cancer Research. 2012 ; Vol. 72, No. 22. pp. 5790-5800.
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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 signi ficantly 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.",
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Portal-Nunẽz, S, Shankavaram, UT, Rao, M, Datrice, N, Atay, S, Aparicio, M, Camphausen, KA, Fernández-Salguero, PM, Chang, H, Lin, P, Schrump, DS, Garantziotis, S, Cuttitta, F & Zudaire, E 2012, 'Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice', Cancer Research, vol. 72, no. 22, pp. 5790-5800. https://doi.org/10.1158/0008-5472.CAN-12-0818

Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice. / Portal-Nunẽz, Sergio; Shankavaram, Uma T.; Rao, Mahadev; Datrice, Nicole; Atay, Scott; Aparicio, Marta; Camphausen, Kevin A.; Fernández-Salguero, Pedro M.; Chang, Han; Lin, Pinpin; Schrump, David S.; Garantziotis, Stavros; Cuttitta, Frank; Zudaire, Enrique.

In: Cancer Research, Vol. 72, No. 22, 15.11.2012, p. 5790-5800.

Research output: Contribution to journalArticle

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T1 - Aryl hydrocarbon receptor-induced adrenomedullin mediates cigarette smoke carcinogenicity in humans and mice

AU - Portal-Nunẽz, Sergio

AU - Shankavaram, Uma T.

AU - Rao, Mahadev

AU - Datrice, Nicole

AU - Atay, Scott

AU - Aparicio, Marta

AU - Camphausen, Kevin A.

AU - Fernández-Salguero, Pedro M.

AU - Chang, Han

AU - Lin, Pinpin

AU - Schrump, David S.

AU - Garantziotis, Stavros

AU - Cuttitta, Frank

AU - Zudaire, Enrique

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N2 - 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 signi ficantly 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.

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