title: The balance between 4-hydroxynonenal and intrinsic glutathione/glutathione S-transferase A4 system may be critical for the epidermal growth factor receptor phosphorylation of human esophageal squamous cell carcinomas.
abstract: Oxidative stress might participate in the carcinogenesis of human esophageal squamous cell carcinomas (hESCC). 4-Hydroxynonenal (HNE) is a major product of membrane lipid peroxidation with short life. It might act as an important mediator through the generation of adducts and activate epidermal growth factor receptor (EGFR) signaling. It is mainly trapped with glutathione (GSH) and catalyzed by glutathione S-transferases (GSTs). This study aimed to elucidate the possible participation of HNE, GSH/GST system, and EGFR signaling in hESCC development. Immunohistochemistry of HNE adducts, EGFR, and phosphorylated EGFR (pEGFR) was performed with hESCC specimens. The effect of HNE on the phosphorylation of EGFR and its downstream PhospholipaseCγ1 (PLCγ1) was investigated with KYSE30 cell-line. Pretreatment with GSH inducer N-acetylcysteine (NAC) or GSH inhibitor Buthionine sulfoximine (BSO) and mandatory transfection of hGSTA4 gene in KYSE30 were conducted to investigate the relationship between HNE and GSH/GST system. Immunoreactants of HNE adducts, EGFR, and pEGFR were increased in hESCC compared to non-cancerous epithelium with positive correlations. The treatment of HNE ligand-independently induced the phosphorylation of EGFR and PLCγ1 accompanying the diminishment of intracellular GSH level. NAC increased GSH contents but BSO decreased in dose-dependent manners. Reflecting changes in GSH, HNE-induced EGFR phosphorylation was suppressed by NAC, whereas it was promoted by BSO. Mandatory expression of hGSTA4 suppressed HNE-induced events. We first demonstrated that the ligand-independent activation of EGFR by the balance between the stimulation of HNE and the prevention of intrinsic GSH/GST system might participate in the development of hESCC.
authors.affiliation: Division of Gastroenterology, Tohoku Graduate School of Medicine, Sendai, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Uno
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Kato
authors.forename: Gen
authors.initials: G
authors.lastname: Kusaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000963:Antimetabolites / Q000494:pharmacology; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D000963:Antimetabolites; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D019328:Buthionine Sulfoximine; D005982:Glutathione Transferase; D066246:ErbB Receptors; C041116:leukotriene-C4 synthase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine