Efficacy of 5-aminolevulinic acid–based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway
| Autor: | Jun Liu, Huiping Chen, Xiaorong Ma, Miao Xu, Yan Xiao, Tianxiang Ouyang, Tao Liu, Yingying Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mitochondrial ROS 3-TYP 3-(1H-1 2 3-triazol-4-yl)pyridine Light Clinical Biochemistry Apoptosis Biochemistry 5-ALA 5-aminolevulinic acid chemistry.chemical_compound 0302 clinical medicine SRT1720 Sirtuin 1 NAD nicotinamide adenine dinucleotide Sirtuin 3 skin and connective tissue diseases lcsh:QH301-705.5 lcsh:R5-920 Photosensitizing Agents Chemistry Superoxide mROS mitochondrial reactive oxygen species IP immunoprecipitation PDT photodynamic therapy 5-aminolevulinic acid Keloid lcsh:Medicine (General) Signal Transduction Research Paper Programmed cell death SIRT3 SIRT1 sirtuin 1 SOD2 SOD2 superoxide dismutase 2 mitochondrial 03 medical and health sciences ROS reactive oxygen species SIRT1 FBS fetal bovine serum Autophagy Humans SQSTM1/p62 sequestosome 1 SIRT3 sirtuin 3 Superoxide Dismutase Organic Chemistry Fibroblasts Levulinic Acids Oxidative Stress 030104 developmental biology Photochemotherapy lcsh:Biology (General) Cancer research Reactive Oxygen Species 030217 neurology & neurosurgery 3-MA 3-methyladenine |
| Zdroj: | Redox Biology, Vol 20, Iss, Pp 195-203 (2019) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Keloids exhibit cancer-like properties without spontaneous regression and usually recur post excision. Although photodynamic therapy (PDT) is a promising treatment, details of the mechanisms remain to be elucidated. In this study, we investigated mechanisms involved in 5-Aminolevulinic Acid (5-ALA)–based PDT against keloid. Found that 5-ALA-PDT induced superoxide anion-dependent autophagic cell death. Application of autophagy inhibitor 3-Methyladenine (3-MA) significantly prevented the effect that 5-ALA-PDT induced keloid–derived fibroblasts death, but Z-VAK-FMK (apoptotic inhibitor) did not. Interestingly, 5-ALA-PDT promoted the SIRT3 protein expression and the activity of mitochondrial superoxide dismutase 2 (SOD2), but SIRT1 protein expression level was decreased. SOD2 as a key enzyme can decrease mitochondrial ROS (mROS) level, Deacetylation of SOD2 by SIRT3 regulates SOD2 enzymatic activity has been identified. Then we explored SOD2 acetylation level with immunoprecipitation, found that 5-ALA-PDT significantly increased the acetylation levels of SOD2. In order to confirm deacetylation of SOD2 regulated by SIRT3, 3-TYP (SIRT3 inhibitor) was used. Found that inhibition of SIRT3 by 3-TYP significantly increased the level of SOD2 acetylation level compared with control group or 5-ALA-PDT group. To explore the connection of SIRT1 and SIRT3, cells were treated with EX527(SIRT1 inhibitor) or SRT1720 (SIRT1 activator), and EX527 increased SIRT3 protein level, however, SRT1720 displayed the opposite effect in the present or absence of 5-ALA-PDT. Moreover SIRT1-inhibited cells are more resistant to 5-ALA-PDT and showing decreased ROS accumulation. These results may demonstrate that 5-ALA-PDT induced SIRT1 protein level decreased, which promoted the effect of SIRT3 increased activity of SOD2 that can reduce mROS level, and then compromised 5-ALA-PDT induced autophagic cell death. Keywords: Keloid, 5-aminolevulinic acid, SIRT1, SIRT3, Autophagy |
| Databáze: | OpenAIRE |
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