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Published on: January 9, 2019
Phenethyl isothiocyanate sensitizes glioma cells to TRAIL-induced apoptosis
Dae-Hee Lee1, Dong-Wook Kim2, Hai-Chon Lee3
1Department of Neurosurgery, University of Virginia, School of Medicine, USA.
Abstract:
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is a promising antitumor therapy. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Here we show that in combination with phenethyl isothiocyanate (PEITC), exposure to TRAIL induced apoptosis in TRAIL-resistant glioma cells. Subtoxic concentrations of PEITC significantly potentiated TRAIL-induced cytotoxicity and apoptosis in glioma cells. PEITC dramatically upregulated DR5 receptor expression but had no effects on DR4 receptor. PEITC enhances TRAIL-induced apoptosis through the downregulation of cell survival proteins and the upregulation of DR5 receptors through actions on the ROS-induced-p53.
Insights
Phenethyl isothiocyanate (PEITC) overcomes TRAIL resistance in malignant glioma cells. PEITC enhances TRAIL-induced apoptosis by upregulating DR5 receptors and downregulating survival proteins.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapy
Background:
- Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows promise as an antitumor therapy.
- Malignant glioma cells often exhibit resistance to TRAIL, necessitating strategies to enhance its efficacy.
Purpose of the Study:
- To investigate the potential of phenethyl isothiocyanate (PEITC) in overcoming TRAIL resistance in glioma cells.
- To elucidate the molecular mechanisms underlying PEITC's potentiation of TRAIL-induced apoptosis.
Main Methods:
- Treatment of TRAIL-resistant glioma cells with TRAIL in combination with varying concentrations of PEITC.
- Assessment of cytotoxicity and apoptosis induction.
- Analysis of DR4 and DR5 receptor expression levels.
- Evaluation of cell survival and death signaling pathways, including ROS-induced-p53.
Main Results:
- Subtoxic concentrations of PEITC significantly enhanced TRAIL-induced cytotoxicity and apoptosis in resistant glioma cells.
- PEITC markedly upregulated the expression of the DR5 receptor, while DR4 receptor expression remained unaffected.
- PEITC promoted TRAIL-induced apoptosis by downregulating pro-survival proteins and upregulating DR5 via ROS-induced-p53 signaling.
Conclusions:
- PEITC is a potent sensitizer of TRAIL-resistant glioma cells.
- The combination of PEITC and TRAIL represents a promising therapeutic strategy for malignant gliomas.
- Upregulation of DR5 and modulation of survival pathways are key mechanisms mediating PEITC's effect.
