The adenosine-A2a receptor regulates the radioresistance of gastric cancer via PI3K-AKT-mTOR pathway

Background: Radiotherapy is a key strategy in gastric Cancer (GC) treatment. However, radioresistance remains a serious concern. It is unclear whether the accumulation of adenosine A2a receptor (ADO-A2aR) is related to radioresistance in GC. In this study, the molecular role of ADO-A2aR in GC radioresistance was investigated.

Methods: Colony formation assays were used to assess the role of ADO-A2aR on radioresistance. GC stem cell surface marker expression (including Nanog, OCT-4, SOX-2 and CD44) and PI3K/Akt/mTOR signaling pathway associated protein levels (including phosphorylated PI3K, phosphorylated Akt and phosphorylated mTOR) were determined via western blotting, flow cytometry and immunofluorescence. In addition, the role of ADO-A2aR on radioresistance was explored in vivo using murine xenograft models.

Results: ADO-A2aR regulated GC cell stemness both in vitro and in vivo. This was shown to induce radioresistance in GC. ADO-A2aR was revealed to significantly induce cell cycle arrest and promote GC cell Apoptosis. These activities were closely linked to activation of the PI3K/Akt/mTOR pathway.

Conclusion: This study identified that ADO enhances GC cell stemness via interaction with A2aR and subsequent activation of the PI3K/Akt/mTOR pathway. Ultimately, this resulted in radioresistance. A2aR is a potential target to improve GC radiosensitivity.