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Loss of glutathione peroxidase 7 promotes TNF-?-induced NF-?B activation in Barrett's carcinogenesis.

ABSTRACT: Esophageal adenocarcinoma (EAC) is a classic example of inflammation-associated cancer, which develops through GERD (gastroesophageal reflux disease)-Barrett's esophagus (BE)-dysplasia-adenocarcinoma sequence. The incidence of EAC has been rising rapidly in the USA and Western countries during the last few decades. The functions of glutathione peroxidase 7 (GPX7), an antioxidant enzyme frequently silenced during Barrett's tumorigenesis, remain largely uncharacterized. In this study, we investigated the potential role of GPX7 in regulating nuclear factor-kappaB (NF-?B) activity in esophageal cells. Western blot analysis, immunofluorescence and luciferase reporter assay data indicated that reconstitution of GPX7 expression in CP-A (non-dysplastic BE cells) and FLO-1 (EAC cells) abrogated tumor necrosis factor-? (TNF-?)-induced NF-?B transcriptional activity (P < 0.01) and nuclear translocation of NF-?B-p65 (P = 0.01). In addition, we detected a marked reduction in phosphorylation levels of components of NF-?B signaling pathway, p-p65 (S536), p-I?B-? (S32) and p-IKK?/? (S176/180), as well as significant suppression in induction of NF-?B target genes [TNF-?, interleukin (IL)-6, IL-8, IL-1?, CXCL-1 and CXCL-2] following treatment with TNF-? in GPX7-expressing FLO-1 cells as compared with control cells. We validated these effects by knockdown of GPX7 expression in HET1A (normal esophageal squamous cells). We found that GPX7-mediated suppression of NF-?B is independent of reactive oxygen species level and GPX7 antioxidant function. Further mechanistic investigations demonstrated that GPX7 promotes protein degradation of TNF-receptor 1 (TNFR1) and TNF receptor-associated factor 2 (TRAF2), suggesting that GPX7 modulates critical upstream regulators of NF-?B. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-?-induced activation of proinflammatory NF-?B signaling, a major player in GERD-associated Barrett's carcinogenesis.

SUBMITTER: Peng DF

PROVIDER: S-EPMC4076814 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis.

Peng Dun-Fa DF Hu Tian-Ling TL Soutto Mohammed M Belkhiri Abbes A El-Rifai Wael W

Carcinogenesis 20140401 7

Esophageal adenocarcinoma (EAC) is a classic example of inflammation-associated cancer, which develops through GERD (gastroesophageal reflux disease)-Barrett's esophagus (BE)-dysplasia-adenocarcinoma sequence. The incidence of EAC has been rising rapidly in the USA and Western countries during the last few decades. The functions of glutathione peroxidase 7 (GPX7), an antioxidant enzyme frequently silenced during Barrett's tumorigenesis, remain largely uncharacterized. In this study, we investiga ...[more]

PMID: 24692067

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Project description:Glutathione peroxidase 1 (GPX1) is a crucial antioxidant enzyme that prevented the harmful accumulation of intra-cellular hydrogen peroxide. GPX1 might contribute in limiting cochlear damages associated with aging or acoustic overexposure, but the function of GPX1 in the inner ear remains unclear. The present study was designed to investigate the effect of GPX1 on cochlear spiral ganglion neurons (SGNs) against oxidative stress induced by peroxynitrite, a versatile oxidant generated by the reaction of superoxide anion and nitric oxide. Here, we first found that the expression of GPX1 in cultured SGNs was downregulated after peroxynitrite exposure. Then, the GPX1 mimic ebselen and the gpx1 knockout (gpx1 -/-) mice were used to investigate the role of GPX1 in SGNs treated with peroxynitrite. The pretreatment with ebselen significantly increased the survived SGN numbers, inhibited the apoptosis, and enhanced the expression of 4-HNE in the cultured SGNs of peroxynitrite + ebselen group compared with the peroxynitrite-only group. On the contrary, remarkably less survived SGNs, more apoptotic SGNs, and the higher expression level of 4-HNE were detected in the peroxynitrite + gpx1 -/- group compared with the peroxynitrite-only group. Furthermore, rescue experiments with antioxidant N-acetylcysteine (NAC) showed that the expression of 4-HNE and the apoptosis in SGNs were significantly decreased, while the number of surviving SGNs was increased in peroxynitrite + NAC group compared the peroxynitrite-only group and in peroxynitrite + gpx1 -/- + NAC group vs. peroxynitrite + gpx1 -/- group. Finally, mechanistic studies showed that the activation of nuclear factor-kappa B (NF-κB) was involved in the SGNs damage caused by peroxynitrite and that GPX1 protected SGNs against peroxynitrite-induced damage, at least in part, via blocking the NF-κB pathway activation. Collectively, our findings suggest that GPX1 might serve as a new target for the prevention of nitrogen radical-induced SGNs damage and hearing loss.

Dataset Information

Loss of glutathione peroxidase 7 promotes TNF-?-induced NF-?B activation in Barrett's carcinogenesis.

Publications

Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis.

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