Autophagy induced by cathepsin S inhibition induces early ROS production, oxidative DNA damage, and cell death via xanthine oxidase

Chien Chang Huang, Kuo Li Chen, Chun Hei Antonio Cheung, Jang Yang Chang

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

Cathepsin S plays multiple roles in MHC class II antigen presentation, extracellular matrix degradation, angiogenesis, and tumorogenesis. Our previous study revealed that targeting cathepsin S could induce cellular cytotoxicity and reduce cell viability. For the current study, we further investigated the molecular mechanism responsible for targeting cathepsin S-induced cell death and its association with autophagy. Distinct from regulation of the classic autophagy pathway by reactive oxygen species (ROS), we demonstrated that autophagy is the genuine regulator of early ROS production. The molecular silencing of autophagy-dependent ATG genes (ATG5, ATG7, and LC3) and the pharmacologic inhibition of autophagy with 3-MA and wortmannin reduced ROS production significantly. In addition, xanthine oxidase (XO), which is upregulated by autophagy, is required for early ROS production, oxidative DNA damage, and consequent cell death. Autophagy inhibition suppresses the upregulation of XO, which is induced by cathepsin S inhibition, resulting in reduced ROS generation, DNA damage, and cell death. Collectively, our study reveals a noncanonical molecular pathway in which, after the inhibition of cathepsin S, autophagy induces early ROS production for oxidative DNA damage and cell death through XO.

Original languageEnglish
Pages (from-to)1473-1486
Number of pages14
JournalFree Radical Biology and Medicine
Volume65
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords

  • Autophagy
  • Cathepsin S
  • DNA damage
  • Early ROS
  • Xanthine oxidase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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