Shi Chung-Sheng, Kuan Feng-Che, Chin Chih-Chien, Li Jhy-Ming
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan, Taiwan.
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital Chiayi, Taiwan.
Am J Cancer Res. 2023 Aug 15;13(8):3741-3752. eCollection 2023.
Colorectal cancer (CRC) is one of the leading causes of malignancy-related deaths worldwide. Radiotherapy is often combined with surgery to treat patients with more advanced CRC. Despite impressive initial clinical responses, radiotherapy resistance is the main reason for most treatment failures in colorectal cancer. The G protein-coupled adrenergic receptor (AR) has shown to involve in the development and radiotherapy resistance of CRC. The β2-AR blockage (ICI-118,551) can use to inhibit the progression of CRC through downregulating EGFR-Akt-ERK1/2 signaling. Since catecholamines-activated the G protein-coupled AR activation has been shown to result in radioresistant, co-treatment with both β2-AR blockage and radiation may be improved the clinical outcome of CRC. We demonstrated that selective β2-AR blockage, but not selective β1-AR blockage, significantly enhanced radiation-induced apoptosis in CRC cells with wild-type . The molecular mechanism of the apoptotic pathway was possibly triggered by a change in the mitochondrial membrane permeability and release of cytosolic cytochrome C through phospho-P53 mitochondrial translocation. We also found that a P53 knockout in the HCT116 cells was correlated with reversing β2-AR blockage-mediated apoptosis induction after radiation treatment. Furthermore, the β2-AR blockage significantly inhibited CRC cell-xenograft growth . Our study suggests that β2-AR blockage may be used as adjunct agent for improving the clinical outcomes of CRC following radiotherapy by inducing apoptosis in CRC cells.
结直肠癌（CRC）是全球恶性肿瘤相关死亡的主要原因之一。放疗常与手术联合用于治疗更晚期的CRC患者。尽管初始临床反应令人印象深刻，但放疗抵抗是大多数结直肠癌治疗失败的主要原因。G蛋白偶联肾上腺素能受体（AR）已被证明参与CRC的发生发展和放疗抵抗。β2-AR阻断剂（ICI-118,551）可通过下调EGFR-Akt-ERK1/2信号通路来抑制CRC的进展。由于儿茶酚胺激活G蛋白偶联AR已被证明会导致放射抗性，β2-AR阻断剂与放疗联合治疗可能会改善CRC的临床结局。我们证明，选择性β2-AR阻断而非选择性β1-AR阻断，能显著增强野生型CRC细胞的辐射诱导凋亡。凋亡途径的分子机制可能是由线粒体膜通透性的改变以及通过磷酸化P53线粒体易位导致的胞质细胞色素C的释放所触发。我们还发现，HCT116细胞中的P53基因敲除与放疗后β2-AR阻断介导的凋亡诱导的逆转相关。此外，β2-AR阻断剂显著抑制CRC细胞异种移植瘤的生长。我们的研究表明，β2-AR阻断剂可作为辅助药物，通过诱导CRC细胞凋亡来改善CRC放疗后的临床结局。
