Reactive Oxygen Species Mediate 6c-Induced Mitochondrial and Lysosomal Dysfunction, Autophagic Cell Death, and DNA Damage in Hepatocellular Carcinoma
| Autor: | Delu Che, Songqiang Xie, Ronghui Fan, Senzhen Wang, Yuxia Wang, Lei Gao, Mengke Gao, Yongli Feng, Fujun Dai, Chaojie Wang, Xiaojuan Xu, Chaochao Ge, Yue Cao, Jinghua Li |
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| Rok vydání: | 2021 |
| Předmět: |
Proteomics
Mitochondrial ROS Programmed cell death Carcinoma Hepatocellular Proteome QH301-705.5 DNA damage Autophagic Cell Death Mitochondrion Antioxidants Article Catalysis Inorganic Chemistry lysosomes Sequestosome-1 Protein Humans Biology (General) Physical and Theoretical Chemistry QD1-999 Molecular Biology Spectroscopy reactive oxygen species chemistry.chemical_classification Reactive oxygen species Chemistry Adenine Liver Neoplasms Organic Chemistry Autophagy Autophagosomes Hep G2 Cells General Medicine Acetylcysteine Mitochondria Computer Science Applications Cell biology Comet assay Naphthalimides Cancer cell Microtubule-Associated Proteins |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 20 International Journal of Molecular Sciences, Vol 22, Iss 10987, p 10987 (2021) |
| ISSN: | 1422-0067 |
| Popis: | Increasing the level of reactive oxygen species (ROS) in cancer cells has been suggested as a viable approach to cancer therapy. Our previous study has demonstrated that mitochondria-targeted flavone-naphthalimide-polyamine conjugate 6c elevates the level of ROS in cancer cells. However, the detailed role of ROS in 6c-treated cancer cells is not clearly stated. The biological effects and in-depth mechanisms of 6c in cancer cells need to be further investigated. In this study, we confirmed that mitochondria are the main source of 6c-induced ROS, as demonstrated by an increase in 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox fluorescence. Compound 6c-induced mitochondrial ROS caused mitochondrial dysfunction and lysosomal destabilization confirmed by absolute quantitation (iTRAQ)-based comparative proteomics. Compound 6c-induced metabolic pathway dysfunction and lysosomal destabilization was attenuated by N-acetyl-L-cysteine (NAC). iTRAQ-based comparative proteomics showed that ROS regulated the expression of 6c-mediated proteins, and treatment with 6c promoted the formation of autophagosomes depending on ROS. Compound 6c-induced DNA damage was characterized by comet assay, p53 phosphorylation, and γH2A.X, which was diminished by pretreatment with NAC. Compound 6c-induced cell death was partially reversed by 3-methyladenine (3-MA), bafilomycin (BAF) A1, and NAC, respectively. Taken together, the data obtained in our study highlighted the involvement of mitochondrial ROS in 6c-induced autophagic cell death, mitochondrial and lysosomal dysfunction, and DNA damage. |
| Databáze: | OpenAIRE |
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