Rapamycin affects radiosensitivity of colorectal cancer by activating the autophagy of M2 macrophage
10.3760/cma.j.cn112271-20220606-00240
- VernacularTitle:雷帕霉素激活M2巨噬细胞自噬影响大肠癌放射敏感性的研究
- Author:
Lening SHAO
1
;
Baosong ZHU
;
Xiaodong YANG
;
Jianping CAO
;
Chungen XING
Author Information
1. 苏州大学附属第二医院胃肠外科，苏州 215004
- Keywords:
Rapamycin;
M2 macrophages;
Autophagy;
Colorectal cancer;
Radiation sensitivity
- From:
Chinese Journal of Radiological Medicine and Protection
2022;42(9):657-663
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the effects of rapamycin on the autophagy activation of M2 macrophages and the radiosensitivity in colorectal cancer xenograft.Methods:THP-1 cells were induced into Type-Ⅱ macrophages with PMA and/or IL-4. Rapamycin and Bafilomycin A1 were uesd to activate and suppress autophagy of M2 macrophage, respectively. Colorectal cancer LoVo cells were inoculated on BALB/c-nu/nu nude mice. After the xenograft tumor size approached to 10 mm in diameter, the nude mice were divided into the following groups randomly: M2 macrophage autophagy inactive group and active group, autophagy downregulation of the activated group, and nontreatment control group. The tumors in mice were irradiated with 8 Gy X-rays in two fractions, and the radiosensitivity of colorectal cancer xenograft in each group was analyzed.Results:The expression levels of M2 macrophage markers Arg-1 and CCL-22 were significantly higher than those in M0 macrophage. The tumor weight, volume [(1.93±0.05)g, (2.14±0.06)cm 3] and micro-vessel density (36.37±1.04) in M2 autophagy inactive group were higher than those in control group [(1.35±0.05)g, (1.77±0.02)cm 3, 25.69±1.34] ( t=20.07, 14.56, 10.92, P < 0.05). After activation of M2 autophagy, the tumor weight, volume and micro-vessel density were significantly decreased to (0.89±0.03)g, (1.24±0.01)cm 3, and 13.60±1.52 ( t=44.37, 40.32, 21.43, P < 0.05). After down-regulation of M2 autophagy with bafilomycin A1, the tumor weight, volume and micro-vessel density were increased to (1.02±0.07)g, (1.37±0.02)cm 3, and 21.06±1.41 ( t=4.67, 13.79, 6.23, P < 0.05). Autophagy inaction suppressed the expression of Livin and Survivin in tumor ( t=2.64, 7.90, P < 0.05), and the activation of M2 autophagy further down-regulated the expression of Livin, Survivin ( t=5.43, 9.39, P < 0.05). The expression levels of Livin and Survivin were increased after the treatment with bafilomycin A1 ( t=2.80, 3.17, P<0.05). Conclusions:M2 macrophagy promoted the growth of colorectal cancer xenograft by inducing the formation of micro-vessels in the tumor, which is one of the mechanisms of tumor-associated macrophages participating in the radiotherapy resistance of colorectal cancer. Activation of M2 autophagy by rapamycin inhibited the ability of M2 macrophagy in promoting tumor growth, and induced apoptosis of colorectal cancer cells after radiotherapy by down-regulating the expression of anti-apoptotic genes Livin and Survivin, thus increased the radiosensitivity of colorectal cancer.
