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

Jorgensen E, Stinson A, Shan L, Yang J, Gietl D, Albino AP - BMC Cancer (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Public Health Division, Vector Research LLC, New York, NY, USA. ejorgensen@vectorgroupltd.com

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.

Conclusion: 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.

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Related in: MedlinePlus

Representative immunohistochemical expression features of phospho-eIF2α, eIF2α, and BiP proteins in different human lung lesions. The proteins assessed by immunohistochemistry are designated in rows, while the columns depict expression in normal lung tissues, representative positive (ISI values of > 6–9) and negative NSCLCs, and representative positive (ISI values of > 6–9) and negative Small Cell Carcinomas. Magnification, ×200.
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Figure 12: Representative immunohistochemical expression features of phospho-eIF2α, eIF2α, and BiP proteins in different human lung lesions. The proteins assessed by immunohistochemistry are designated in rows, while the columns depict expression in normal lung tissues, representative positive (ISI values of > 6–9) and negative NSCLCs, and representative positive (ISI values of > 6–9) and negative Small Cell Carcinomas. Magnification, ×200.

Mentions: Representative immunohistochemical features of phospho-eIF2α staining are shown in Figure 12. Table 2 summarizes the immunoreactivity data and the statistical analysis detailed in Table 3 indicates a significant difference (p = 0.0025) between the mean phospho-eIF2α immunohistochemical staining indices (ISIs) for the non-small cell carcinoma diagnostic group and the normal diagnostic group. Of the 93 assessable cases of NSCLCs, 52 (55.9%) showed a significant increase in expression of phospho-eIF2α with an ISI between > 1–12 with many of these showing intense staining. There were no statistically significant differences in phospho-eIF2α expression between the normal diagnostic group and either the small cell lung carcinoma (SCLC) or mixed carcinoma (MC) diagnostic groups. Table 4 compares the ISI levels in the tumor compartment to the ISI levels in the normal compartment for each of the carcinoma diagnostic groups. The data indicate a statistically significant difference in expression of phospho-eIF2α between the malignant and non-malignant cellular compartments of both the NSCLC (p = < 0.0001) and MC (p = 0.0324) diagnostic groups, but not the SCLC (p = 0.1833) diagnostic group.


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

Jorgensen E, Stinson A, Shan L, Yang J, Gietl D, Albino AP - BMC Cancer (2008)

Representative immunohistochemical expression features of phospho-eIF2α, eIF2α, and BiP proteins in different human lung lesions. The proteins assessed by immunohistochemistry are designated in rows, while the columns depict expression in normal lung tissues, representative positive (ISI values of > 6–9) and negative NSCLCs, and representative positive (ISI values of > 6–9) and negative Small Cell Carcinomas. Magnification, ×200.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2527015&req=5

Figure 12: Representative immunohistochemical expression features of phospho-eIF2α, eIF2α, and BiP proteins in different human lung lesions. The proteins assessed by immunohistochemistry are designated in rows, while the columns depict expression in normal lung tissues, representative positive (ISI values of > 6–9) and negative NSCLCs, and representative positive (ISI values of > 6–9) and negative Small Cell Carcinomas. Magnification, ×200.
Mentions: Representative immunohistochemical features of phospho-eIF2α staining are shown in Figure 12. Table 2 summarizes the immunoreactivity data and the statistical analysis detailed in Table 3 indicates a significant difference (p = 0.0025) between the mean phospho-eIF2α immunohistochemical staining indices (ISIs) for the non-small cell carcinoma diagnostic group and the normal diagnostic group. Of the 93 assessable cases of NSCLCs, 52 (55.9%) showed a significant increase in expression of phospho-eIF2α with an ISI between > 1–12 with many of these showing intense staining. There were no statistically significant differences in phospho-eIF2α expression between the normal diagnostic group and either the small cell lung carcinoma (SCLC) or mixed carcinoma (MC) diagnostic groups. Table 4 compares the ISI levels in the tumor compartment to the ISI levels in the normal compartment for each of the carcinoma diagnostic groups. The data indicate a statistically significant difference in expression of phospho-eIF2α between the malignant and non-malignant cellular compartments of both the NSCLC (p = < 0.0001) and MC (p = 0.0324) diagnostic groups, but not the SCLC (p = 0.1833) diagnostic group.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Public Health Division, Vector Research LLC, New York, NY, USA. ejorgensen@vectorgroupltd.com

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus