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

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BMC Cancer

, 8:229

First Online: 11 August 2008Received: 05 March 2008Accepted: 11 August 2008DOI: 10.1186-1471-2407-8-229

Cite this article as: Jorgensen, E., Stinson, A., Shan, L. et al. BMC Cancer 2008 8: 229. doi:10.1186-1471-2407-8-229


BackgroundAlthough 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.

MethodsGene 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.

ResultsWe 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.

ConclusionThese 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.

AbbreviationsAJCCAmerican Joint Committee on Cancer

ATF6activation transcription factor 6

BiPbinding immunoglobulin protein

CScigarette smoke


ERendoplasmic reticulum

eIF2αeukaryotic translation initiation factor 2-alpha

phospho-eIF2αphospho-eukaryotic translation initiation factor 2-alpha

FTCfederal trade commission

ISIimmunohistochemical staining index

NSCLCnon-small cell lung carcinoma

PCRpolymerase chain reaction

SCCsquamous cell carcinoma

UPRunfolded protein response

XBP1X-box binding protein.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-8-229 contains supplementary material, which is available to authorized users.

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Author: Ellen Jorgensen - Andy Stinson - Lin Shan - Jin Yang - Diana Gietl - Anthony P Albino


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