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 Shin, Ju Hong Jeon, Kyungho Choi, In Gyu Kim

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)235-241
Number of pages7
JournalMolecules and Cells
Volume33
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Doxorubicin
Cell Death
transglutaminase 2
Toll-Like Receptor 2
Blocking Antibodies
Egtazic Acid
Acetylcysteine
Post Translational Protein Processing
Caffeine
Drug Resistance
Cell Adhesion
DNA Damage
Reperfusion
Reactive Oxygen Species
Cell Survival
Oxidative Stress
Ischemia
Apoptosis

Keywords

  • Activation
  • Doxorubicin
  • Intracellular activity
  • Transglutaminase 2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Doxorubicin induces the persistent activation of intracellular transglutaminase 2 that protects from cell death. / Cho, Sung Yup; Jeong, Eui Man; Lee, Jin Haeng; Kim, Hyo Jun; Lim, Jisun; Kim, Chai Wan; Shin, Dong Myung; Jeon, Ju Hong; Choi, Kyungho; Kim, In Gyu.

In: Molecules and Cells, Vol. 33, No. 3, 03.2012, p. 235-241.

Research output: Contribution to journalArticle

Cho, SY, Jeong, EM, Lee, JH, Kim, HJ, Lim, J, Kim, CW, Shin, DM, Jeon, JH, Choi, K & Kim, IG 2012, 'Doxorubicin induces the persistent activation of intracellular transglutaminase 2 that protects from cell death', Molecules and Cells, vol. 33, no. 3, pp. 235-241. https://doi.org/10.1007/s10059-012-2201-9
Cho, Sung Yup ; Jeong, Eui Man ; Lee, Jin Haeng ; Kim, Hyo Jun ; Lim, Jisun ; Kim, Chai Wan ; Shin, Dong Myung ; Jeon, Ju Hong ; Choi, Kyungho ; Kim, In Gyu. / Doxorubicin induces the persistent activation of intracellular transglutaminase 2 that protects from cell death. In: Molecules and Cells. 2012 ; Vol. 33, No. 3. pp. 235-241.
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