title: Doxorubicin induces the persistent activation of intracellular transglutaminase 2 that protects from cell death.
abstract: The activation of transglutaminase 2 (TG2), an enzyme that catalyzes post-translational modifications of proteins, has been implicated in apoptosis, cell adhesion and inflammatory responses. We previously reported that intracellular TG2 is activated under oxidative stress conditions, such as ultraviolet irradiation, ischemia-reperfusion, and hypoxia. In this study, we examined the effect of genotoxic stress on the intracellular activity of TG2 using doxorubicin which generates reactive oxygen species that lead to double-strand breakage of DNA. We demonstrated that doxorubicin elicits the persistent activation of TG2. Doxorubicin-induced TG2 activity was suppressed by treatment with caffeine at the early phase, N-acetylcysteine at the mid-phase, and EGTA at the late phase. However, treatment with a blocking antibody against TGFβ or toll-like receptor 2 showed no effect on TG2 activity, indicating that at least three different signaling pathways may be involved in the process of TG2 activation. In addition, using MEF cells defective for TG2 and cells overexpressing an activesite mutant of TG2, we revealed that doxorubicin-induced cell death is inversely correlated with TG2 activity. Our findings indicate that the persistent activation of TG2 by doxorubicin contributes to cell survival, suggesting that the mechanism-based inhibition of TG2 may be a novel strategy to prevent drug-resistance in doxorubicin treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Sung-Yup
authors.initials: SY
authors.lastname: Cho
authors.forename: Eui Man
authors.initials: EM
authors.lastname: Jeong
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Lee
authors.forename: Hyo-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jisun
authors.initials: J
authors.lastname: Lim
authors.forename: Chai-Wan
authors.initials: CW
authors.lastname: Kim
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Shin
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.forename: Kyungho
authors.initials: K
authors.lastname: Choi
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction / Q000187:drug effects; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D020536:Enzyme Activators; D002110:Caffeine; D004533:Egtazic Acid; D004317:Doxorubicin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins