title: Overexpression of the μ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis.
abstract: BACKGROUND
  Recent epidemiologic studies suggesting that there were differences in cancer recurrence contingent on anesthetic regimens have raised the possibility that μ-opioid agonists can influence cancer progression. Based on our previous studies indicating the μ-opioid receptor (MOR) is up-regulated in several types of non-small cell lung cancer, this study examined the functional significance of MOR overexpression to elucidate a possible mechanism for the epidemiologic findings.
  
  
  METHODS
  Stable vector control and MOR1 overexpressing human bronchioloalveolar carcinoma cells were evaluated using immunoblot analysis, proliferation and transendothelial extravasation assays with or without Akt inhibitor, mTOR inhibitor (temsirolimus), or the peripheral MOR antagonist, methylnaltrexone. In human lung cancer xenograft models, primary tumor growth rates and lung metastasis were analyzed using consecutive tumor volume measurements and nestin immunoreactivity in lungs of the nude mouse model.
  
  
  RESULTS
  The authors provide evidence that MOR is an important regulator of lung cancer progression. MOR overexpression increased Akt and mTOR activation, proliferation, and extravasation in human bronchioloalveolar carcinoma cells. In vivo, overexpression of MOR in human bronchoalveolar carcinoma cells increased primary tumor growth rates in nude mice by approximately 2.5-fold and lung metastasis by approximately 20-fold compared with vector control cells (n = 4 per condition).
  
  
  CONCLUSIONS
  The overexpression data suggest a possible direct effect of MOR on Akt and mTOR activation and lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings. The authors' observations further suggest that exploration of MOR in non-small cell lung carcinoma merits further study both as a diagnostic and therapeutic option.
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.forename: Bolot
authors.initials: B
authors.lastname: Mambetsariev
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moss
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017450:Receptors, Opioid, mu; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases