title: Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells.
abstract: BACKGROUND
  Although lung cancer is among the few malignancies for which we know the primary etiological agent (i.e., cigarette smoke), a precise understanding of the temporal sequence of events that drive tumor progression remains elusive. In addition to finding that cigarette smoke (CS) impacts the functioning of key pathways with significant roles in redox homeostasis, xenobiotic detoxification, cell cycle control, and endoplasmic reticulum (ER) functioning, our data highlighted a defensive role for the unfolded protein response (UPR) program. The UPR promotes cell survival by reducing the accumulation of aberrantly folded proteins through translation arrest, production of chaperone proteins, and increased degradation. Importance of the UPR in maintaining tissue health is evidenced by the fact that a chronic increase in defective protein structures plays a pathogenic role in diabetes, cardiovascular disease, Alzheimer's and Parkinson's syndromes, and cancer.
  
  
  METHODS
  Gene and protein expression changes in CS exposed human cell cultures were monitored by high-density microarrays and Western blot analysis. Tissue arrays containing samples from 110 lung cancers were probed with antibodies to proteins of interest using immunohistochemistry.
  
  
  RESULTS
  We show that: 1) CS induces ER stress and activates components of the UPR; 2) reactive species in CS that promote oxidative stress are primarily responsible for UPR activation; 3) CS exposure results in increased expression of several genes with significant roles in attenuating oxidative stress; and 4) several major UPR regulators are increased either in expression (i.e., BiP and eIF2 alpha) or phosphorylation (i.e., phospho-eIF2 alpha) in a majority of human lung cancers.
  
  
  CONCLUSIONS
  These data indicate that chronic ER stress and recruitment of one or more UPR effector arms upon exposure to CS may play a pivotal role in the etiology or progression of lung cancers, and that phospho-eIF2 alpha and BiP may have diagnostic and/or therapeutic potential. Furthermore, we speculate that upregulation of UPR regulators (in particular BiP) may provide a pro-survival advantage by increasing resistance to cytotoxic stresses such as hypoxia and chemotherapeutic drugs, and that UPR induction is a potential mechanism that could be attenuated or reversed resulting in a more efficacious treatment strategy for lung cancer.
authors.affiliation: Public Health Division, Vector Research LLC, New York, NY, USA. ejorgensen@vectorgroupltd.com
authors.forename: Ellen
authors.initials: E
authors.lastname: Jorgensen
authors.forename: Andy
authors.initials: A
authors.lastname: Stinson
authors.forename: Lin
authors.initials: L
authors.lastname: Shan
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.forename: Diana
authors.initials: D
authors.lastname: Gietl
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Albino
mesh_terms: D000328:Adult; D000368:Aged; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D018384:Oxidative Stress; D011489:Protein Denaturation; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects*
chemical_list: D004791:Enzyme Inhibitors; D012906:Smoke