Different redox states in malignant and nonmalignant esophageal epithelial cells and differential cytotoxic responses to bile acid and honokiol.
Esophageal adenocarcinoma (EAC) is a highly lethal cancer in western countries. EAC cells are believed to develop from esophageal epithelial cells through complex transformation processes involving inflammation and oxidative stress. The purpose of this study was to compare the redox status of malignant and nonmalignant esophageal epithelial cells and to test their responses to bile acid-induced oxidative stress and to treatment with honokiol (HNK), a natural product with anticancer activity. We demonstrated that esophageal adenocarcinoma cells express significantly higher levels of antioxidant molecules and were resistant to reactive oxygen species (ROS) stress induced by bile acid, but were sensitive to the cytotoxic action of HNK. Mechanistic study showed that HNK caused cancer cell death by disruption of mitochondrial transmembrane potential and was correlated with cyclophilin D (CypD) expression. Inhibition of CypD by cyclosporin A or abrogation of its expression by siRNA significantly suppressed the cytotoxicity of HNK, suggesting that CypD may be a key molecule that mediates the cytotoxicity. Our study suggests that the high antioxidant capacity in EAC cells confers on them the ability to survive the oxidative microenvironment in the reflux esophagus, and that HNK is a promising compound to kill the transformed cells preferentially.
Chen
Gang
G
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Izzo
Julie
J
Demizu
Yusuke
Y
Wang
Feng
F
Guha
Sushovan
S
Wu
Xifeng
X
Hung
Mein-Chie
MC
Ajani
Jaffer A
JA
Huang
Peng
P
D000230:Adenocarcinoma / Q000473:pathology; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002461:Cell Line, Transformed; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000473:pathology*; D004947:Esophagus / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering; D000498:Allyl Compounds; D010636:Phenols
D001647:Bile Acids and Salts; D001713:Biphenyl Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D017705:Lignans; D034741:RNA, Small Interfering; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols