Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells

Kode, Aruna; Saravanan, R.; Caito, Samuel; Yang, Se‐Ran; Megson, Ian L.; Rahman, Irfan

doi:10.1152/ajplung.00361.2007

Cited by 397 publications

(285 citation statements)

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“…It has been demonstrated that exposure to CSE induces oxidative stress and causes activation of Nrf2 in lung cells. 17,18 In this study, we demonstrated that although exposure to high concentrations of CSE inhibited cell proliferation, low concentrations of CSE enhanced NCI-H292 cell proliferation and Nrf2 activation. These findings suggest that low levels of oxidative stress enhance Nrf2-mediated cell proliferation in NSCLC cells whose EGFR gene and Keap1 genes are wild type.…”

Section: Discussionmentioning

confidence: 54%

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

et al. 2012

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We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes.

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Section: Discussionmentioning

confidence: 54%

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

et al. 2012

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“…Recently, a redox-sensitive transcription factor, Nrf2, has been suggested to be an interesting target to intervene in the progression of experimental COPD/emphysema (43). However, it remains to be seen how effective Nrf2 activators will be in the treatment of COPD/emphysema, as it is posttranslationally modified, destabilized, and degraded in lungs of patients with COPD, and in rodent lungs exposed to CS (44)(45)(46)(47). In light of this, we compared the efficacy of SOD mimetic with NAC on elastase-induced emphysema in WT C57BL/6J and SOD3 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O 2 • ─ . ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m 3 ) to 6 mo (100 mg/m 3 total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.antioxidants | cigarette smoke | chronic obstructive pulmonary disease | oxidants | glutathione E xtracellular superoxide dismutase (ECSOD or SOD3) is one of the three SOD antioxidant enzyme isoforms, and is highly expressed in lungs and vessels (1, 2). It is located in the ECM, the junctions of airway epithelial cells, the surface of airway smooth muscle, and the lining of vessels of the lung. SOD3 functions as a superoxide anion scavenger, thereby attenuating oxidative stress, which may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Acute loss of SOD3 in adult mice causes death, whereas low mortality rates are seen in SOD3-overexpressing animals exposed to hyperoxia, suggesting an essential role of SOD3 for survival (3,4). Accumulating evidence shows that SOD3 polymorphism is associated with a decline in lung function in rodents and humans, and susceptibility to COPD, which may be a result of alteration of its encoding protein structure, function, and level (5-14). However, it is unclear whether endogenous SOD3 participates in the development/ progression of the inflammatory response, leading to COPD/ emphysema.Cigarette smoke (CS) is the major etiological factor in the pathogenesis of COPD, which is characterized by chronic lung inflammation, parenchymal destruction (i.e., emphysema), and accelerated decline in lung function....

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“…Aside from affecting selectively phase I enzymes, resveratrol also stimulates the expression and activity of phase II enzymes. Supplementation of resveratrol in the medium of different cell types resulted in increased expression and activation of NQO1 [67], increased HO-1 expression and increased cellular glutathione content [68,69].…”

Section: Molecular Targets Of Resveratrolmentioning

confidence: 99%

Anticancer Activities of Resveratrol in Colorectal Cancer

Schaafsma¹,

Hsieh²,

Doonan³

et al. 2016

Biol Med (Aligarh)

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Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a dietary polyphenolic phytochemical that has demonstrated health benefits such as cardioprotection, the prevention of neurodegeneration and chemoprevention. Resveratrol has shown great potential in the prevention and treatment of carcinomas and clinical trials support resveratrol as anticancer compound in colorectal carcinoma. Colorectal cancer remains a major cause of cancer-related deaths for both men and women in industrialized countries. Because of this widespread prevalence, identifying major risk factors and initiating colorectal screening procedures provide the distinct advantage for recognizing early disease and addressing treatable forms of CRC. Epidemiological studies of fruit and vegetable consumption in relationship to developing CRC have led to the notion that safe and inexpensive chemopreventive agents might be a valuable tool in diminishing the morbidity and mortality of CRC. While clinical trials and in vivo data show positive effects of resveratrol in CRC, the mechanism of action is relatively unclear. In this review, we will evaluate the current literature on the actions of resveratrol in CRC and provide a more mechanistic view of resveratrol in relationship with CRC.

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Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells

Cited by 397 publications

References 56 publications

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Anticancer Activities of Resveratrol in Colorectal Cancer

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