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Involvement of A2B Receptor in DNA Damage Response and Radiosensitizing Effect of A2B Receptor Antagonists on Mouse
Yuta Tanaka1, Kazuki Kitabatake1, Ryo Abe2,3
1Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
Abstract:
It is therapeutically important to elucidate the factors involved in the radiation resistance of tumors. We previously showed that ATP is released from mouse melanoma B16 cells in response to γ-irradiation, but the role of adenosine, a metabolite of ATP, is still unclear. Here, we show that the adenosine A2B receptor is involved in DNA damage repair and radioresistance in mouse melanoma B16 cells. The DNA damage response after γ-irradiation was attenuated by pretreatment with A2B receptor antagonists, such as PSB603, while it was enhanced by pretreatment with A2B receptor agonists, such as BAY60-6583. γ-Irradiation decreased the cell survival rate, and pretreatment with PSB603 further reduced the survival rate. On the other hand, pretreatment with BAY60-6583 increased the cell survival rate after irradiation. The DNA damage response and the cell survival rate after γ-irradiation were both decreased in A2B-knockdown cells. In vivo experiments in mice confirmed that tumor growth was suppressed and delayed in the irradiated group pretreated with PSB603, compared with the irradiation-alone group. Our results indicate that adenosine A2B receptor contributes to radioresistance, and could be a new target for the development of agents to increase the efficacy of radiotherapy.
Insights
Adenosine A2B receptor plays a key role in tumor radioresistance by influencing DNA damage repair and cell survival. Targeting this receptor could enhance radiotherapy efficacy for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Tumor radiation resistance is a critical therapeutic challenge.
- Previous studies identified ATP release from melanoma cells upon irradiation.
- The role of adenosine, an ATP metabolite, in radioresistance remained unclear.
Purpose of the Study:
- To investigate the involvement of the adenosine A2B receptor in DNA damage repair and radioresistance of mouse melanoma B16 cells.
- To determine if adenosine A2B receptor modulation affects cell survival and tumor growth post-irradiation.
Main Methods:
- Utilized A2B receptor antagonists (PSB603) and agonists (BAY60-6583) in mouse melanoma B16 cell cultures.
- Assessed DNA damage response and cell survival rates after gamma-irradiation.
- Performed in vivo experiments using A2B-knockdown cells and antagonist treatment in mice bearing tumors.
Main Results:
- A2B receptor antagonists attenuated DNA damage response and reduced cell survival post-irradiation.
- A2B receptor agonists enhanced DNA damage response and increased cell survival.
- A2B receptor knockdown decreased both DNA damage response and cell survival.
- In vivo, antagonist treatment suppressed and delayed tumor growth in irradiated mice.
Conclusions:
- Adenosine A2B receptor significantly contributes to melanoma radioresistance.
- Modulating A2B receptor activity impacts DNA repair and cell survival following radiation.
- The adenosine A2B receptor represents a potential therapeutic target for improving radiotherapy outcomes.
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