Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells

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.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 eIF2α) or phosphorylation (i.e., phospho-eIF2α) in a majority of human lung cancers.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-eIF2α 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.The long lag time between initiation of cigarette smoking and cancer induction (estimated at 25 to 50 pack-years) [1,2] raises several fundamental questions concerning the eventual induction of tobacco-induced diseases for which there is little information: e.g., how does the lung adapt to the chronic assault of many decades of cigarette smoke (CS) exposure, what are the biological sequelae that occur in response to this adaptation and the continuous disruption of normal cellular homeostasis in the lung, and is this adaption a help or hindrance to lung cancer development? Our working hypothesis is that a) tobacco-induced lun