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Non-Thermal Plasma Couples Oxidative Stress to TRAIL Sensitization through DR5 Upregulation
Soon Young Hwang1, Ngoc Hoan Nguyen1, Tae Jung Kim2
1Department of Life Sciences, College of Natural Sciences, Ajou University, Suwon 16499, Korea.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells without affecting most normal cells. Despite being in clinical testing, novel strategies to induce TRAIL-mediated apoptosis are in need to overcome cancer cell unresponsiveness and resistance. Plasma-activated medium (PAM) markedly stimulates reactive oxygen/nitrogen species (ROS/RNS)-dependent apoptosis in cancer cells. We investigate the capability of PAM and TRAIL (PAM/TRAIL) combination therapy to overcome TRAIL resistance and improve the anticancer efficacy of TRAIL. The combinatorial treatment of PAM and TRAIL shows synergistic effects on growth inhibition in TRAIL-resistant cancer cells via augmented apoptosis by two attributes. DR5 (TRAIL-R2) transcription by CHOP is upregulated in a PAM-generated ROS/RNS-dependent manner, and PAM itself upregulates PTEN expression mediated by suppression of miR-425 which is involved in Akt inactivation, leading to increased apoptosis induction. Treatment of cancer cell lines with the antioxidant N-acetylcysteine reduces the extent of membrane dysfunction and the expression of both CHOP-DR5 and miR-425-PTEN axes, attenuating PAM/TRAIL-induced cancer cell apoptosis. These data suggest that PAM/TRAIL treatment is a novel approach to sensitizing cancer cells to TRAIL-induced apoptosis and overcoming TRAIL resistance. PAM is a promising candidate for further investigations as a chemotherapeutic sensitizer in the treatment of cancer.
Insights
Plasma-activated medium (PAM) combined with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) synergistically enhances cancer cell apoptosis. This novel combination therapy overcomes TRAIL resistance by upregulating DR5 and PTEN expression, offering a promising approach for cancer treatment.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell apoptosis but faces challenges with resistance.
- Plasma-activated medium (PAM) stimulates apoptosis in cancer cells via reactive oxygen/nitrogen species (ROS/RNS).
- Novel strategies are needed to enhance TRAIL efficacy and overcome cancer cell resistance.
Purpose of the Study:
- To investigate the combination therapy of PAM and TRAIL (PAM/TRAIL) for overcoming TRAIL resistance.
- To elucidate the mechanisms underlying the synergistic effects of PAM/TRAIL on cancer cell apoptosis.
- To evaluate PAM as a potential chemotherapeutic sensitizer.
Main Methods:
- Treatment of TRAIL-resistant cancer cells with PAM and TRAIL.
- Analysis of apoptosis induction, DR5 and PTEN expression, and miR-425 levels.
- Assessment of the effects of the antioxidant N-acetylcysteine on PAM/TRAIL-induced apoptosis.
Main Results:
- PAM/TRAIL combination therapy demonstrated synergistic growth inhibition and augmented apoptosis in TRAIL-resistant cancer cells.
- PAM upregulated DR5 transcription via CHOP and PTEN expression by suppressing miR-425, dependent on ROS/RNS.
- N-acetylcysteine treatment attenuated PAM/TRAIL-induced apoptosis, confirming the roles of ROS/RNS and the identified molecular axes.
Conclusions:
- PAM/TRAIL combination therapy is a novel approach to sensitize cancer cells to TRAIL-induced apoptosis and overcome resistance.
- The synergistic effect involves ROS/RNS-dependent upregulation of the CHOP-DR5 axis and miR-425-PTEN axis.
- PAM shows promise as a chemotherapeutic sensitizer for cancer treatment.
