Naringin Induces Lysosomal Permeabilization and Autophagy Cell Death in AGS Gastric Cancer Cells
| Autor: | Silvia Yumnam, Suchismita Raha, Won Sup Lee, Venu Venkatarame Gowda Saralamma, Sang Eun Ha, Seong Min Kim, Gon Sup Kim, Ho Jeong Lee |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
Cell Membrane Permeability Down-Regulation Cathepsin D Mitochondrial Membrane Transport Proteins Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Stomach Neoplasms Lysosome Autophagy Tumor Cells Cultured medicine Humans Naringin PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Chemistry TOR Serine-Threonine Kinases General Medicine Cell biology Lysosomal lumen medicine.anatomical_structure Complementary and alternative medicine 030220 oncology & carcinogenesis Flavanones Cancer cell Lysosomes Microtubule-Associated Proteins Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The American Journal of Chinese Medicine. 48:679-702 |
| ISSN: | 1793-6853 0192-415X |
| Popis: | Autophagy is a process of active programmed cell death, where a dying cell induces autophagosomes and subsequently regulated by degradative machinery. The aim of this study was to investigate the mechanism behind induction of autophagic cell death by Naringin flavonoid in AGS cancer cells. Growth inhibition of AGS cells showed downregulation of PI3K/Akt/mTOR signaling by Naringin treatment. Transmission electron microscopy observation showed swollen mitochondria and lysosome near peri-nuclear zone fused with autophagic vacuoles. Rapamycin pre-treatment with Naringin showed significant decrease in mTOR phosphorylation and increase in LC3B activation in AGS cells. Decrease in mTOR phosphorylation is associated with lysosomal function activation was observed by time-dependent treatment of Naringin. Induction of lysosomal membrane permeabilization (LMP) was observed by LAMP1 activation leading lysosomal cell death by releasing Cathepsin D from lysosomal lumen to cytosol. Naringin treated AGS cells showed up-regulating BH3 domain Bad, down-regulating Bcl-xL, and Bad phosphorylation and significant mitochondrial fluorescence intensity expression. Significant localization of mitochondria and LC3B activation was examined by person coefficient correlation. Activation of ERK1/2-p38 MAPKs and production of intracellular ROS has been observed over Naringin treatment. It has also been elucidated that pre-treatment with NAC inhibited mitochondria-LC3B colocalization, where ROS acted as upstream of ERK1/2-p38 MAPKs activation. Lysosomal cell death involvement has been evaluated by BAF A1 pre-treatment, inhibiting LAMP1, Cathepsin D, ROS, and blocking autophagolysosome in AGS cell death. Taken together, these findings show that, Naringin induced autophagy cell death involves LMP mediated lysosomal damage and BH3 protein Bad activation in AGS cancer cells. |
| Databáze: | OpenAIRE |
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