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Mesencephalic astrocyte-derived neurotrophic factor is a novel radioresistance factor in mouse B16 melanoma
Yuta Tanaka1, Takato Takenouchi2, Mitsutoshi Tsukimoto1
1Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-0022, Japan.
Abstract:
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor produced in response to endoplasmic reticulum (ER) stress induced by various stressors, but its involvement in the radioresistance of tumor cells is unknown. Here, we found that MANF is released after γ-irradiation (2 Gy and 4 Gy) of B16 melanoma cells, and its release was suppressed by 4-phenylbutyric acid, an ER stress inhibitor. MANF was not released after low-dose (1 Gy) γ-irradiation, but pretreatment of 1 Gy-irradiated cells with recombinant MANF enhanced the cellular DNA damage response and attenuated reproductive cell death. In MANF-knockdown cells, the DNA damage response and p53 activation by γ-irradiation (2 Gy) were suppressed, and reproductive cell death was increased. MANF also activated the ERK signaling pathway. Our findings raise the possibility that MANF could be a new target for overcoming radioresistance.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) aids tumor cells in surviving radiation. MANF enhances DNA repair and reduces cell death, suggesting it as a target to overcome radioresistance.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) is known for neuroprotection during endoplasmic reticulum (ER) stress.
- The role of MANF in tumor cell radioresistance remains unexplored.
Purpose of the Study:
- To investigate the involvement of MANF in the radioresistance of B16 melanoma cells.
- To explore MANF's potential as a therapeutic target for enhancing radiotherapy efficacy.
Main Methods:
- γ-irradiation of B16 melanoma cells at varying doses (1-4 Gy).
- Treatment with 4-phenylbutyric acid (ER stress inhibitor) and recombinant MANF.
- Assessment of MANF release, DNA damage response, p53 activation, reproductive cell death, and ERK signaling pathway activation.
- MANF-knockdown cell experiments.
Main Results:
- MANF is released from B16 melanoma cells following 2 Gy and 4 Gy γ-irradiation, suppressed by ER stress inhibitor.
- Low-dose (1 Gy) irradiation did not induce MANF release, but MANF pretreatment enhanced DNA damage response and reduced cell death.
- MANF knockdown suppressed DNA damage response and p53 activation, increasing reproductive cell death after 2 Gy irradiation.
- MANF was found to activate the ERK signaling pathway.
Conclusions:
- MANF plays a significant role in mediating radioresistance in tumor cells.
- MANF enhances DNA damage response and survival pathways, potentially contributing to treatment failure.
- MANF emerges as a potential therapeutic target for overcoming tumor radioresistance in cancer treatment.
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