Autophagy has been reported to play a radioresistance role in high-dose-rate irradiation. However, its mechanisms and roles in continuous low-dose-rate (CLDR) irradiation have not been clearly understood. Iodine-125 (I-125) seed brachytherapy is a modality of CLDR irradiation and has been used in the treatment of various cancers. In this study, we investigated the mechanisms and roles of autophagy induced by I-125 seed radiation in human esophageal squamous cell carcinoma (ESCC) cell lines (Eca-109 and EC-109) and a xenograft mouse model. The results of this work showed that I-125 seed radiation induced a dose-dependent increase in autophagy in both cell lines. In Eca-109 cells, I-125 seed radiation-induced endoplasmic reticulum (ER) stress, manifesting as the increased levels of intracellular Ca²⁺ and Grp78/BiP, and activated PERK-eIF2α, IRE1, and ATF6 pathways of the unfolded protein response. Knockdown of PERK led to the decreased expression of autophagy marker, LC3B-II. Inhibition of autophagy by chloroquine or knockdown of ATG5 enhanced I-125 seed radiation-induced cell proliferation inhibition and apoptosis. Interestingly, chloroquine did not aggravate ER stress but promoted apoptosis via the mitochondrial pathway. The animal experiment showed that inhibition of autophagy by chloroquine improved the efficacy of I-125 seed radiation. In summary, our data demonstrate that I-125 seed CLDR radiation induces ER stress-mediated autophagy in ESCC. Autophagy plays a pro-survival role in I-125 seed CLDR irradiation, and chloroquine is a potential candidate for use in combination therapy with I-125 seed radiation treatment to improve efficacy against ESCC.

据报道自噬在高剂量率辐射中具有抗辐射作用。但是，其在连续低剂量率（CLDR）照射中的机制和作用还不清楚。碘125（I-125）种子近距离放射疗法是CLDR照射的一种方式，已用于治疗各种癌症。在这项研究中，我们调查了I-125种子辐射在人食道鳞状细胞癌（ESCC）细胞系（Eca-109和EC-109）和异种移植小鼠模型中诱导自噬的机制和作用。这项工作的结果表明，I-125种子辐射可诱导两种细胞系中自噬的剂量依赖性增加。在Eca-109细胞中，I-125种子辐射诱导的内质网（ER）应激，表现为细胞内Ca ²⁺水平的升高和Grp78 / BiP，以及激活的PERK-eIF2α，IRE1和ATF6途径的未折叠蛋白反应。抑制PERK导致自噬标记物LC3B-II的表达降低。氯喹抑制自噬或抑制ATG5增强了I-125种子辐射诱导的细胞增殖抑制和凋亡。有趣的是，氯喹并没有加重内质网应激，而是通过线粒体途径促进了细胞凋亡。动物实验表明，氯喹对自噬的抑制作用提高了I-125种子辐射的功效。总之，我们的数据表明I-125种子CLDR辐射可诱导ESCC内质网应激介导的自噬。自噬在I-125种子CLDR辐射中具有促进生存的作用，氯喹是与I-125种子放射治疗联合治疗以提高抗ESCC功效的潜在候选者。