B Cell Translocation Gene 2 Enhances Susceptibility of HeLa Cells to Doxorubicin-induced Oxidative Damage

• Published in: The Journal of biological chemistry 2008-11, Vol.283 (48), p.33110-33118
• Main Authors: Lim, Young-Bin, Park, Tae Jun, Lim, In Kyoung
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Apoptosis - drug effects; Apoptosis - genetics; Catalase - genetics; Catalase - metabolism; Chromatin - genetics; Chromatin - metabolism; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Free Radical Scavengers - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; HeLa Cells; Humans; Hydrogen Peroxide - metabolism; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Lamin Type A - genetics; Lamin Type A - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Mechanisms of Signal Transduction; Oxidative Stress - drug effects; Oxidative Stress - genetics; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804255200

BTG2/TIS21/PC3 (B cell translocation gene 2) has been known as a p53 target gene and functions as a tumor suppressor in carcinogenesis of thymus, prostate, kidney, and liver. Although it has been known that the expression of BTG2/TIS21/PC3 is induced during chemotherapy-mediated apoptosis in cancer cells, a role of BTG2/TIS21/PC3 in cell death remains to be elucidated. In this study, the mechanism and role of BTG2 involved in the enhancement of doxorubicin (DOXO)-induced cell death were examined. Treatment of HeLa cells with DOXO revealed apoptotic phenomena, such as chromatin condensation and cleavage of poly(ADP-ribose) polymerase and lamin A/C with concomitant increase of BTG2/TIS21/PC3 expression. Employing infections of Ad-TIS21 virus and lentivirus with short hairpin RNA to BTG2, the effect of BTG2/TIS21/PC3 on the DOXO-induced apoptosis of HeLa cells and liver cancer cells was evaluated. Not only short hairpin RNA-BTG2 but also N-acetyl-l-cysteine significantly reduced the DOXO-induced HeLa cell death and generation of H2O2. Moreover, forced expression of BTG2/TIS21/PC3 using adenoviral vector augmented DOXO-induced cancer cell death concomitantly with increase of manganese-superoxide dismutase but not catalase, CuZnSOD, and glutathione peroxidase 1. The increased apoptosis by forced expression of BTG2/TIS21/PC3 could be inhibited by N-acetyl-l-cysteine and polyethylene glycol-catalase. These results therefore suggest that BTG2/TIS21/PC3 works as an enhancer of DOXO-induced cell death via accumulation of H2O2 by up-regulating manganese-superoxide dismutase without any other antioxidant enzymes. In summary, BTG2/TIS21/PC3 enhances cancer cell death by accumulating H2O2 via imbalance of the antioxidant enzymes in response to chemotherapy.