title: Silencer-of-Death Domain Mediates Acid-Induced Decrease in Cell Apoptosis in Barrett's Associated Esophageal Adenocarcinoma Cells.
abstract: We have shown that NADPH oxidase (NOX)5-S may mediate the acid-induced decrease in cell apoptosis. However, mechanisms of NOX5-S-dependent decrease in cell apoptosis are not fully understood. In this study, we found that silencer-of-death domain (SODD) was significantly increased in esophageal adenocarcinoma (EA) tissues, EA cell lines FLO and OE33, and a dysplastic cell line CP-B. Strong SODD immunostaining was significantly higher in low-grade dysplasia (66.7%), high-grade dysplasia (81.2%), and EA (71.2%) than in Barrett's mucosa (10.5%). Acid treatment significantly increased SODD protein and mRNA expression and promoter activity in FLO cells, an increase that was significantly decreased by the knockdown of NOX5-S and nuclear factor κB (NF-κB)1 p50 with their small interfering RNAs. Similarly, acid-induced increase of SODD mRNA was blocked by knockdown of NOX5-S and p50 in a BE cell line CP-A. Overexpression of NOX5-S significantly increased SODD protein expression in FLO cells. Moreover, overexpression of NOX5-S or p50 significantly increased the SODD promoter activity and decreased the caspase 9 activity or apoptosis. NOX5-S overexpression-induced increase in SODD promoter activity was significantly decreased by knockdown of p50. In addition, acid treatment significantly decreased the caspase 9 activity, a decrease that was significantly inhibited by knockdown of SODD. Furthermore, chromatin immunoprecipitation assay showed that NF-κB1 p50 bound to SODD genomic DNA containing a NF-κB-binding element GGGGACACCCT. This binding element was further confirmed by a gel mobility shift assay. We conclude that acid-induced increase in SODD expression and decrease in cell apoptosis may depend on the activation of NOX5-S and NF-κB1 p50 in FLO cells.
authors.affiliation: Departments of Medicine (D.L., W.C.) and Pathology (W.C.), Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island; and Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China (J.H.).
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Departments of Medicine (D.L., W.C.) and Pathology (W.C.), Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island; and Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China (J.H.).
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: Departments of Medicine (D.L., W.C.) and Pathology (W.C.), Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island; and Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China (J.H.) weibiao_cao@brown.edu.
authors.forename: Weibiao
authors.initials: W
authors.lastname: Cao
mesh_terms: D000143:Acids / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000150:complications* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000150:complications*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000150:complications* / Q000473:pathology*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000378:metabolism; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000143:Acids; D048868:Adaptor Proteins, Signal Transducing; C116906:BAG4 protein, human; D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human