Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult

• Published in: Biochemical pharmacology Vol. 73; no. 6; pp. 782 - 792
• Main Authors: Yeh, Ting-Chun, Chiang, Po-Cheng, Li, Tsai-Kun, Hsu, Jui-Ling, Lin, Chun-Jung, Wang, Shih-Wei, Peng, Chieh-Yu, Guh, Jih-Hwa
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.03.2007; Elsevier Science
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptotic Protease-Activating Factor 1 - physiology; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Caspases - physiology; Cell Line, Tumor; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Flavonoid; GADD153; Gastroenterology. Liver. Pancreas. Abdomen; Genistein; Genistein - pharmacology; Heat-Shock Proteins - genetics; Heat-Shock Proteins - physiology; Hepatocellular carcinoma; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Chaperones - genetics; Molecular Chaperones - physiology; Pharmacology. Drug treatments; Reactive Oxygen Species - metabolism; Transcription Factor CHOP - genetics; Transcription Factor CHOP - physiology; Tumors; Hepatocellular carcinoma; Mitochondria; Flavonoid; Endoplasmic reticulum; Genistein; GADD153; Human; Interaction; Hepatic disease; Malignant tumor; Isoflavone derivatives; Stress; Hepatocellular carcinoma Flavonoid Genistein Endoplasmic reticulum Mitochondria GADD153; Liver cancer; Polyphenol; Cell death; Phenols; Digestive diseases; Apoptosis
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2006.11.027

Hepatocellular carcinoma is a very common malignancy and is chemoresistant to currently available chemotherapeutic agents. Endoplasmic reticulum (ER) stress-induced apoptotic pathway is suggested to be less affected by the resistance mechanisms, becoming a potential target of chemotherapeutic strategy. The anticancer effects and expression of GADD153, a transcription factor induced by ER stress, were examined in hepatocellular carcinoma Hep3B cells. The correlation between these two parameters was constructed under flavonoid stimulation with a correlation coefficient ( r) of 0.8. The data also showed that genistein (isoflavone) was the most effective one. Genistein induced the activation of several ER stress-relevant regulators, including m-calpain, GADD153, GRP78 and caspase-12. Furthermore, genistein-induced effect was inhibited in cells transfected with antisense GADD153 cDNA, indicating a functional role of GADD153. Notably, genistein induced the activation of caspase-2, whereas did not cause the DNA damage. It also triggered the production of ROS. The antioxidant trolox significantly reduced ROS accumulation, but did not modify genistein-induced apoptotic cell death. The long-term exposure (48 h) of cells to genistein caused Mcl-1 down-regulation and Bad cleavage; furthermore, cyclosporin A (an inhibitor of mitochondrial permeability transition pore) almost completely abolished genistein-induced loss of mitochondrial membrane potential, and induced a 30% reverse of apoptosis caused by long-term treatment (48 h) of genistein, suggesting the involvement of mitochondrial stress in the late phase of genistein-induced effect. Taken together, it is suggested that genistein induces the anticancer effect through a mechanism initiated by ER stress and facilitated by mitochondrial insult in Hep3B cells.