Li Yi, Lu Kui, Zhao Ben, Zeng Xiaokui, Xu Shan, Ma Xin, Zhi Yunqing
Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Oncology, the Second People's Hospital of Taizhou City, Taizhou, China.
J Gastrointest Oncol. 2020 Dec;11(6):1135-1145. doi: 10.21037/jgo-20-210.
Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC.
Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting.
Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells .
This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.
尽管晚期结直肠癌（CRC）的放射治疗对某些患者非常有效，但治疗耐药性限制了其疗效。胰岛素样生长因子1受体（IGF1R）可影响多种癌症类型的肿瘤反应性和对辐射的敏感性。在此，我们研究了IGF1R在晚期CRC对放射治疗耐药中的潜在作用，以及使用靶向IGF1R的药物克服CRC患者这种耐药性的可能性。
评估了放射敏感或放射抵抗患者的CRC样本中IGF1R表达水平的差异。选择两种放射抵抗的结肠癌细胞系SW480和HT29进行研究，通过靶向小干扰RNA（siRNA）抑制其表达以及使用特异性IGF1R抑制剂BMS-754807来阐明IGF1R在其放射抵抗中的作用。我们通过检测这些人结肠癌细胞系的增殖、集落形成以及细胞周期分析来评估放射敏感性。使用蛋白质免疫印迹法评估Akt信号通路的激活情况。
与放射敏感患者的组织相比，放射抵抗的结直肠癌患者中IGF1R表达水平更高，而BMS-754807提高了两种结肠癌细胞系的放射敏感性并逆转了放射耐受性。照射前用BMS-754807预处理可抑制Akt磷酸化，诱导细胞周期停滞，并增加DNA损伤。因此，IGF1R促成了CRC细胞的放射抵抗。
本研究支持这样一种观点，即通过直接靶向IGF-1R的表达或活性可以增强放射抵抗的结直肠癌细胞的放射敏感性。最终，放射治疗与IGF1R靶向抑制剂联合使用可能会提高其在晚期结直肠癌治疗中的有效性。
