Autophagy-Regulated ROS from Xanthine Oxidase Acts as an Early Effector for Triggering Late Mitochondria-Dependent Apoptosis in Cathepsin S-Targeted Tumor Cells

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.

The role of autophagy in the pathogenesis of periodontal disease

“…CTSS is mostly produced by immune cells, such as macrophages, B-lymphocytes, and dendritic cells, and is shown to be induced by inflammation (Hsing & Rudensky, 2005;Petanceska, Canoll, & Devi, 1996). The inhibition of CTSS induces the autophagy via several different pathways (such as ROS, p38 MAPK/JNK, EGFR-ERK, and PI3K/Akt/mTOR; Chen et al, 2012;Hsieh et al, 2017;Huang et al, 2015;Zhang, Wang, Xu, Zhu, & Ding, 2014). In vitro study, Memmert et al reported an increased level of CTSS expression in the inflammatory PDLCs induced by IL-1β.…”

Redox regulation of autophagy in skeletal muscle

“…Impairment of autophagy leads to cytosolic-accumulation of ubiquitinated proteins that induces mitochondrial damage and promotes ROS generation (143). In squamous cell carcinoma cells autophagy was shown to increases ROS generation from xanthine oxidase, leading to mitochondrial damage and exacerbating oxidative stress (144). Keap1 (Kelch-like ECH- associated protein 1) binds Nrf2 (nuclear factor erythroid 2-related factor 2), sequestering Nrf2 in the cytoplasm and preventing transcriptional regulation of antioxidant genes.…”

Mesenchymal stem cells promote cell invasion and migration and autophagy‐induced epithelial‐mesenchymal transition in A549 lung adenocarcinoma cells

“…ROS have been reported to regulate starvation‐induced autophagy by regulating the activity of Atg4 . Although ROS is capable of activating autophagy, several studies also demonstrated that autophagy itself could also serve as an early event to induce early ROS production . This indicates that the interplay between MSC coculture‐induced autophagy and ROS generation in A549 cells may be important in the promotion of the invasive and migratory abilities of A549 cells.…”

“…34 Although ROS is capable of activating autophagy, several studies also demonstrated that autophagy itself could also serve as an early event to induce early ROS production. 35,36 This indicates that the interplay between MSC coculture-induced autophagy and ROS gener- Future large-scale studies using this microfluidic chip platform will be performed to characterize key paracrine mediator for tumour autophagy and to provide novel insights into tumour biology during MSC/tumour communication. For example, further studies will utilize neutralizing antibodies against paracrine factors secreted by MSCs, such as TGF-β, PGE2, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor-BB, macrophage inflammatory protein-2, interleukin-6, and interleukin-8.…”