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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

An analysis of potential controls on long-term 137Cs accumulation in the sediments of UK lakes

137 Cs has been utilised extensively to investigate catchment sediment dynamics. Its activity can be indicative of sediment derived from surface sources, and its inventory in deposited sediments reflects local fallout, radioactive decay, sediment accumulation and sediment source. Lakes represent ideal depositional environments for the reconstruction of historical sediment dynamics. In the UK, depth profiles and inventories of 137 Cs in lake cores have been investigated in a large number of catchments, but no study has synthesised all of these data to identify national spatial trends. The aim of this study was therefore to determine what can be learnt from 137 Cs inventories and profiles from UK lakes. Analysis revealed that local reference fallout, the rate of linear sediment accumulation (cm year −1 ) and the lake area:catchment area ratio, are the most important factors that control lake 137 Cs inventories. Delivery of mobile 137 Cs to the lake shortly after fallout, dissolved in runoff, or associated with mobilised sediment in transit from the source to the lake, is also likely a major control on inventories, especially on down-core profiles and peak activities. It is possible that dissolved 137 Cs inputs remain important controls on activities in recently deposited sediments, as they are often higher than potential contributing catchment sediment sources. It is also likely that finer particle-size distributions in lake-bed sediments, compared with source materials, increase both activities and inventories. Uncertainties are associated with patterns of sediment deposition on the lake bed and the estimation of local reference fallout, and lakes with low catchment-derived 137 Cs inputs potentially have a comparable or lower inventory than calculated from the estimated reference fallout. Lakes with multiple inlet tributaries and poor mixing of inflows, or an irregular bed shape divided by ridges and depressions, are also likely to display considerable variability in sediment-associated 137 Cs deposition. Despite these uncertainties, 137 Cs depth profiles provide valuable information on sediment sources and dynamics when interpreted carefully in the context of other UK lakes, and in relation to the corresponding catchment and lake characteristics. Several distinctive down-core profiles and inventories reported here yielded valuable insights into catchment sediment dynamics