Cathepsin S plays multiple roles in MHC class II antigen presentation, extracellular matrix degradation, angiogenesis, and tumorogenesis. Pharmacological inhibition of cathepsin S activity not only inhibits tumor invasion and angiogenesis but also reduces cell viability. Herein, we investigate the molecular executioner which responsible for targeting cathepsin S-induced cell death and its association with autophagy. Surprisingly, distinct from the classical regulation of autophagy by ROS, autophagy, rather than mitochondrial process, is the genuine regulator of early ROS production which responsible for consequent oxidative DNA damage and cell death. Molecular silencing of autophagy-dependent ATG genes and pharmacologic inhibition of autophagy with 3-MA and wortmannin significantly reduced ROS production, oxidative DNA damage, and cell death. Collectively, this study reveals a non-canonical molecular pathway where after the inhibition of cathepsin S, autophagy up-regulates ROS production for oxidative DNA damage and subsequently contributes to autophagy-dependent cell death. (This work was supported by the following grants: Department of Health, Taiwan DOH99-TD-C-111-004, National Health Research Institutes CA-101-PP-22, and National Research Program for Biopharmaceuticals 100CAP015-5)

Citation Format: Chien-Chang Huang, Jang-Yang Chang. Autophagy induced by cathepsin S inhibition causes early ROS production for oxidative DNA damage and subsequent cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1661. doi:10.1158/1538-7445.AM2013-1661