title: 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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC.
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC.
authors.forename: Cheng-Che
authors.initials: CC
authors.lastname: Lee
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC; The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Hsiao-Han
authors.initials: HH
authors.lastname: Lin
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC.
authors.forename: Mei-Chi
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D011480:Protease Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase; D002403:Cathepsins; D053148:Caspase 3; D053453:Caspase 9; C028217:cathepsin S