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.
日期:
2013-04
關聯:
Cancer Research. 2013 Apr;73(8 Suppl. 1):Abstract number 1661.
