Abstract
Cathepsin S (CTSS), which is highly expressed in various malignant tumor cells, has been proposed to promote tumor progression, migration, and invasion. CTSS inhibition not only blocks tumor cell invasion and endothelial tube formation but also induces cellular cytotoxicity. In our previous studies, we have observed that CTSS inhibition induces autophagy, which is responsible for up-regulating xanthine oxidase for early ROS generation and consequent cell death. However, whether the autophagy-regulated early ROS triggers apoptosis remains unclear. We conducted a long-term follow-up study to investigate the relationship between early autophagy and late mitochondria-dependent apoptosis. We demonstrated that early ROS generation is critical for mitochondria damage and the activation of intrinsic apoptotic pathway. Attenuating the early ROS level diminished later mitochondrial damage and downstream apoptotic signaling. Collectively, mitochondria-dependent apoptosis is regulated by autophagy-regulated early ROS, which serves as an early effector that triggers mitochondrial signaling for late apoptosis. The data emphasize the essential role of autophagy-regulated early ROS in triggering late apoptotic signaling.
Highlights
The cysteine proteases, which represent the major group of cathepsins, have recently been indicated to associate with tumor metastasis and recurrence [1,2,3,4]
We recently demonstrated that inhibiting Cathepsin S (CTSS) activities in tumor cells can rapidly induce autophagy [30] and act as an upstream event for mediating early ROS production through xanthine oxidase (XO) [31]
We first examined whether the pharmacological inhibition of CTSS by 6r induces cell cytotoxicity accompanied by apoptosis and autophagy
Summary
The cysteine proteases, which represent the major group of cathepsins, have recently been indicated to associate with tumor metastasis and recurrence [1,2,3,4]. Cathepsin S, known as CTSS, contains an active cysteine residue in the active site for the turnover of intracellular and PLOS ONE | DOI:10.1371/journal.pone.0128045. Connective Evidence between Autophagy and Apoptosis design, data collection and analysis, decision to publish, or preparation of the manuscript Cathepsin S, known as CTSS, contains an active cysteine residue in the active site for the turnover of intracellular and PLOS ONE | DOI:10.1371/journal.pone.0128045 June 1, 2015
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