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B cell translocation gene 2 enhances susceptibility of HeLa cells to doxorubicin-induced oxidative damage.

Authors
Lim, YB; Park, TJ; Lim, IK
Citation
The Journal of biological chemistry, 283(48):33110-33118, 2008
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
Abstract
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.
MeSH terms
Acetylcysteine/pharmacologyAntibiotics, Antineoplastic/pharmacology*Antibiotics, Antineoplastic/therapeutic useApoptosis/drug effectsApoptosis/geneticsCatalase/geneticsCatalase/metabolismChromatin/geneticsChromatin/metabolismDoxorubicin/pharmacology*Doxorubicin/therapeutic useFree Radical Scavengers/pharmacologyGene Expression Regulation, Enzymologic/drug effectsGene Expression Regulation, Enzymologic/geneticsGene Expression Regulation, Neoplastic/drug effectsGene Expression Regulation, Neoplastic/geneticsGenes, Tumor SuppressorGlutathione Peroxidase/geneticsGlutathione Peroxidase/metabolismHela CellsHumansHydrogen Peroxide/metabolismImmediate-Early Proteins/geneticsImmediate-Early Proteins/metabolism*Lamin Type A/geneticsLamin Type A/metabolismLiver Neoplasms/drug therapyLiver Neoplasms/geneticsLiver Neoplasms/metabolism*Oxidative Stress/drug effects*Oxidative Stress/geneticsPoly(ADP-ribose) Polymerases/geneticsPoly(ADP-ribose) Polymerases/metabolismSuperoxide Dismutase/biosynthesisSuperoxide Dismutase/geneticsTumor Suppressor Protein p53/geneticsTumor Suppressor Protein p53/metabolismTumor Suppressor Proteins
DOI
10.1074/jbc.M804255200
PMID
18840609
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > Research Organization > BK21
AJOU Authors
임영빈박태준임인경
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