Citrus-derived DHCP inhibits mitochondrial complex II to enhance TRAIL sensitivity via ROS-induced DR5 upregulation
| Autor: | Hairong Cheng, Lin Sun, Jingmin Yan, Guihua Tai, Yifa Zhou, Miao Hao, Lei Chen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mitochondrial ROS Citrus SQR succinate ubiquinone reductase mitochondrial respiratory chain complex OXPHOS oxidative phosphorylation Cell Apoptosis TRAIL Biochemistry TNF-Related Apoptosis-Inducing Ligand Mice Tumor Cells Cultured OCR oxygen consumption rate Cytotoxicity Caspase Mice Inbred BALB C biology PMS phenazine methosulfate Chemistry Electron Transport Complex II TCA cycle tricarboxylic acid cycle Cell Cycle Cell biology Gene Expression Regulation Neoplastic cell death medicine.anatomical_structure colon cancer Colonic Neoplasms SDH succinate dehydrogenase Female Research Article Programmed cell death GPDH glycerol-3-phosphate dehydrogenase Mice Nude Cyclopentanes ETC electron transfer chain reactive oxygen species (ROS) MTT 3-(4 5-Dimethyl-2-thiazolyl)-2 5-diphenyl-2H-tetrazolium bromide MMP mitochondrial transmembrane potential 03 medical and health sciences ROS reactive oxygen species TMPD tetramethyl-p-phenylene diamine ubiquinone Biomarkers Tumor medicine Animals Humans DR5 Citrus Pectin Molecular Biology Cell Proliferation TRAIL TNF-related apoptosis-inducing ligand 030102 biochemistry & molecular biology G-3-P glycerol-3-phosphate Cell Biology Xenograft Model Antitumor Assays TTFA 4 4 4-trifluoro-1-(2-thienyl)-1 3-butanedione Receptors TNF-Related Apoptosis-Inducing Ligand 030104 developmental biology 3-NPA 3-nitropropionic acid DCPIP 2 6-diclorophenol-indophenol Cancer cell biology.protein Reactive Oxygen Species |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100515 |
| Popis: | Heat-modified citrus pectin, a water-soluble indigestible polysaccharide fiber derived from citrus fruits and modified by temperature treatment, has been reported to exhibit anticancer effects. However, the bioactive fractions and their mechanisms remain unclear. In this current study, we isolated an active compound, trans-4,5-dihydroxy-2-cyclopentene-l-one (DHCP), from heat-treated citrus pectin, and found that is induces cell death in colon cancer cells via induction of mitochondrial ROS. On the molecular level, DHCP triggers ROS production by inhibiting the activity of succinate ubiquinone reductase (SQR) in mitochondrial complex II. Furthermore, cytotoxicity, apoptotic activity, and activation of caspase cascades were determined in HCT116 and HT-29 cell-based systems, the results indicated that DHCP enhances the sensitivity of cancer cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), with DHCP-induced ROS accounting for the synergistic effect between DHCP and TRAIL. Furthermore, the combination of DHCP and TRAIL inhibits the growth of HCT116 and HT-29 xenografts synergistically. ROS significantly increases the expression of TRAIL death receptor 5 (DR5) via the p53 and C/EBP homologous protein pathways. Collectively, our findings indicate that DHCP has a favorable toxicity profile and is a new TRAIL sensitizer that shows promise in the development of pectin-based pharmaceuticals, nutraceuticals, and dietary agents aimed at combating human colon cancer. |
| Databáze: | OpenAIRE |
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