Guihong Liu1,2, Song Yang1,2, Yang Liu2, Yumei Xu1, Hui Qiu1, Jian Sun1,2, Jun Song3,4, Linsen Shi5. 1. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. 2. Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. 3. Departments of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. songjunwk@126.com. 4. Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. songjunwk@126.com. 5. Departments of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu Province, China. shilinsen117@163.com.
Abstract
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.
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.
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