Oxyresveratrol activates parallel apoptotic and autophagic cell death pathways in neuroblastoma cells
Md Ataur Rahman1, Kausik Bishayee1, Ali Sadra1
1Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, South Korea.
Background:
Drug resistance from apoptosis is a challenging issue with different cancer types, and there is an interest in identifying other means of inducing cytotoxicity. Here, treatment of neuroblastoma cells with oxyresveratrol (OXYRES), a natural antioxidant, led to dose-dependent cell death and increased autophagic flux along with activation of caspase-dependent apoptosis.
Methods:
For cell viability, we performed the CCK-8 assay. Protein expression changes were with Western blot and immunocytochemistry. Silencing of proteins was with siRNA. The readouts for cell cycle, mitochondria membrane potential, caspase-3, autophagy and apoptosis were performed with flow cytometry.
Results:
Phosphorylation of p38 MAPK increased with OXYRES treatment and inhibition of p38 reduced autophagy and cell death from OXYRES. In contrast, PI3K/AKT/mTOR signaling decreased in the target cells with OXYRES and inhibition of PI3K or mTOR enhanced OXYRES-mediated cytotoxicity with increased levels of autophagy. Modulation of either of the apoptosis and autophagy flux pathways affected the extent of cell death by OXYRES, but did not affect the indicators of these pathways with respect to each other. Both pathways were independent of ROS generation or p53 activation.
Conclusion:
OXYRES led to cell death from autophagy, which was independent of apoptosis induction. The OXYRES effects were due to changes in the activity levels of p38 MAPK and PI3K/AKT/mTOR.
General Significance:
With two independent and parallel pathways for cytotoxicity induction in target cells, this study puts forward a potential utility for OXYRES or the pathways it represents as novel means of inducing cell death in neuroblastoma cells.
Insights
Oxyresveratrol (OXYRES) induces neuroblastoma cell death through two independent pathways: autophagy and apoptosis. This natural antioxidant offers a potential new strategy for cancer treatment by targeting these distinct cell death mechanisms.
Area of Science:
- * Oncology
- * Molecular Biology
- * Pharmacology
Background:
- * Drug resistance, particularly from apoptosis, poses a significant challenge in various cancer types.
- * Investigating alternative methods for inducing cancer cell death is crucial for developing effective treatments.
- * Neuroblastoma cells treated with oxyresveratrol (OXYRES), a natural antioxidant, exhibited dose-dependent cell death, increased autophagic flux, and activated caspase-dependent apoptosis.
Purpose of the Study:
- * To investigate the mechanisms by which oxyresveratrol (OXYRES) induces cytotoxicity in neuroblastoma cells.
- * To explore the roles of p38 MAPK and PI3K/AKT/mTOR signaling pathways in OXYRES-mediated cell death.
- * To determine the interplay between apoptosis and autophagy in response to OXYRES treatment.
Main Methods:
- * Cell viability was assessed using the CCK-8 assay.
- * Protein expression was analyzed via Western blot and immunocytochemistry.
- * Flow cytometry was employed to measure cell cycle, mitochondrial membrane potential, caspase-3 activity, autophagy, and apoptosis.
- * Protein silencing was achieved using small interfering RNA (siRNA).
Main Results:
- * OXYRES treatment increased p38 MAPK phosphorylation; p38 inhibition reduced OXYRES-induced autophagy and cell death.
- * OXYRES decreased PI3K/AKT/mTOR signaling; PI3K or mTOR inhibition enhanced OXYRES cytotoxicity and autophagy.
- * Both apoptosis and autophagy pathways were modulated by OXYRES independently and were not affected by ROS generation or p53 activation.
Conclusions:
- * Oxyresveratrol (OXYRES) induces neuroblastoma cell death via autophagy, independent of apoptosis induction.
- * OXYRES exerts its effects by altering the activity of p38 MAPK and PI3K/AKT/mTOR signaling pathways.
- * The study highlights OXYRES as a potential therapeutic agent for neuroblastoma, utilizing two distinct and parallel cytotoxicity pathways.
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