Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis

K. Choi, S. W. Ryu, S. Song, H. Choi, S. W. Kang, C. Choi

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33 Scopus citations


Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, causes apoptosis by caspase activation in various cell types, particularly in transformed cells. Numerous types of tumors are relatively resistant to TRAIL-induced cytotoxicity; however, the reasons for this are not yet fully understood. We report here a new signal transduction pathway involving protein kinase Cα (PKCα), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS), that inhibits caspase-dependent cell death induced by TRAIL ligation in human malignant astrocytoma cells. In our experiments, TRAIL ligation-induced generation of intracellular ROS through caspase-dependent proteolytic activation of PKC and subsequent activation of the NOX4 complex. Suppression of intracellular ROS induction using various pharmacological inhibitors or PKCα- or NOX4-specific RNA interference enhanced the enzymatic activity of caspase-3 by blocking the oxidative modification of its catalytic cysteine residue, resulting in marked augmentation of TRAIL-mediated cell death. These results collectively indicate that TRAIL-induced activation of PKCα and NOX4 can modulate TRAIL-mediated apoptosis by promoting oxidative modification of active caspase-3 in a negative-feedback manner.

Original languageEnglish
Pages (from-to)833-845
Number of pages13
JournalCell Death and Differentiation
Issue number5
StatePublished - May 2010

Bibliographical note

Funding Information:
Acknowledgements. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant (R01-2008-000-10701-0) funded by the Ministry of Education, Science and Technology (MEST) and a grant of the Korea Healthcare technology R&D Project (A084215), the Ministry for Health, Welfare & Family Affairs of the Republic of Korea.


  • Apoptosis
  • Caspase
  • Oxidative modification
  • ROS


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