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J. Biol. Chem., Vol. 283, Issue 48, 33110-33118, November 28, 2008

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

From the Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, Korea

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.

Received for publication, June 3, 2008 , and in revised form, October 7, 2008.

^* This work was supported by Research Grants R01-2006-000-10311-0 and M10756040001-07N5604-00110 from the Korea Science and Engineering Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, Korea. Tel.: 82-31-219-5051; Fax: 82-31-219-5059; E-mail: iklim{at}ajou.ac.kr.

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