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Mol. Cells 2012; 33(3): 235-241

Published online February 28, 2012

https://doi.org/10.1007/s10059-012-2201-9

© The Korean Society for Molecular and Cellular Biology

Doxorubicin Induces the Persistent Activation of Intracellular Transglutaminase 2 That Protects from Cell Death

Sung-Yup Cho, Eui Man Jeong, Jin-Haeng Lee, Hyo-Jun Kim, Jisun Lim, Chai-Wan Kim, Dong-Myung Shin1, Ju-Hong Jeon2, Kyungho Choi3, and In-Gyu Kim*

Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea, 1Department of Medicine, Graduate School, University of Ulsan, Seoul 138-736, Korea, 2Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul 110-799, Korea, 3Research Institute of National Cancer Center, Goyang 410-769, Korea

Correspondence to : *Correspondence: igkim@plaza.snu.ac.kr

Received: September 21, 2011; Revised: January 10, 2012; Accepted: January 13, 2012

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 hypo-xia. 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. Doxo-rubicin-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 TGF? 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 active-site 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 treat-ment.

Keywords activation, doxorubicin, intracellular activity, transglutaminase 2

Article

Research Article

Mol. Cells 2012; 33(3): 235-241

Published online March 31, 2012 https://doi.org/10.1007/s10059-012-2201-9

Copyright © The Korean Society for Molecular and Cellular Biology.

Doxorubicin Induces the Persistent Activation of Intracellular Transglutaminase 2 That Protects from Cell Death

Sung-Yup Cho, Eui Man Jeong, Jin-Haeng Lee, Hyo-Jun Kim, Jisun Lim, Chai-Wan Kim, Dong-Myung Shin1, Ju-Hong Jeon2, Kyungho Choi3, and In-Gyu Kim*

Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea, 1Department of Medicine, Graduate School, University of Ulsan, Seoul 138-736, Korea, 2Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul 110-799, Korea, 3Research Institute of National Cancer Center, Goyang 410-769, Korea

Correspondence to:*Correspondence: igkim@plaza.snu.ac.kr

Received: September 21, 2011; Revised: January 10, 2012; Accepted: January 13, 2012

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 hypo-xia. 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. Doxo-rubicin-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 TGF? 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 active-site 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 treat-ment.

Keywords: activation, doxorubicin, intracellular activity, transglutaminase 2

Mol. Cells
Jan 31, 2023 Vol.46 No.1, pp. 1~67
COVER PICTURE
RNAs form diverse shapes and play multiple functions as central molecules of gene expression. In this special issue on RNA, seven minireviews illustrate how basic concepts and recent RNA biology findings are transformed into new and exciting RNA therapeutics.

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