Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG 2) to arsenic trioxide-induced cell death

Changhai Tian, Ping Gao, Yanhua Zheng, Wen Yue, Xiaohui Wang, Haijing Jin, Quan Chen

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Intracellular redox homeostasis plays a critical role in determining tumor cells' sensitivity to drug-induced apoptosis. Here we investigated the role of thioredoxin-1 (TRX1), a key component of redox regulation, in arsenic trioxide (As 2 O 3)-induced apoptosis. Over-expression of wild-type TRX1 in HepG 2 cells led to the inhibition of As 2 O 3 -induced cytochrome c (cyto c) release, caspase activation and apoptosis, and down-regulation of TRX1 expression by RNAi sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. Interestingly, mutation of the active site of TRX1 from Cys 32/35 to Ser 32/35 converted this molecule from an apoptotic protector to an apoptotic promoter. In an effort to understand the mechanisms of this conversion, we used isolated mitochondria from mouse liver and found that recombinant wild-type TRX1 could protect mitochondria from the apoptotic changes. In contrast, the mutant form of TRX1 alone elicited mitochondria-related apoptotic changes, including the mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and cyto c release from mitochondria. These apoptotic effects were inhibited by cyclosporine A (CsA), indicating that mutant TRX1 targeted to mPTP. Alteration of TRX1 from its reduced form to oxidized form in vivo by 2,4- dinitrochlorobenzene (DNCB), a specific inhibitor of TRX reductase, also sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. These data suggest that TRX1 plays a central role in regulating apoptosis by blocking cyto c release, and inactivation of TRX1 by either mutation or oxidization of the active site cysteines may sensitize tumor cells to As 2 O 3 -induced apoptosis.

Original languageEnglish (US)
Pages (from-to)458-471
Number of pages14
JournalCell Research
Volume18
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Apoptosis
  • Arsenic trioxide
  • Cytochrome c
  • Hioredoxin-1
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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