Differential endoplasmic reticulum stress signaling underlies the FLASH effect in human lung epithelial and lung cancer cells
10.3760/cma.j.cn112271-20250710-00242
- VernacularTitle:质子超高剂量率照射对人肺上皮细胞与肺癌细胞系内质网应激通路的差异化调控
- Author:
Xiaofei WANG
1
;
Guangming ZHOU
1
;
Wentao HU
1
Author Information
1. 苏州大学苏州医学院放射医学与防护学院 放射医学与辐射防护国家重点实验室江苏省高校放射医学协同创新中心，苏州 215123
- Publication Type:Journal Article
- Keywords:
Proton FLASH irradiation;
Endoplasmic reticulum stress;
Lung epithelial cells;
Lung cancer cells
- From:
Chinese Journal of Radiological Medicine and Protection
2025;45(11):1138-1143
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the differential responses of the endoplasmic reticulum stress-to-apoptosis cascade induced by proton ultra-high dose rate (FLASH) irradiation between lung epithelial and lung cancer cells.Methods:Human lung epithelial cells (KT) and lung adenocarcinoma cells (A549) were irradiated with protons, and divided into Ctrl, CONV and FLASH groups. Survival curves were generated using colony formation assay. Protein and mRNA expressions of the endoplasmic reticulum (ER) stress and apoptosis regulators were assessed via Western blot and RT-qPCR. The concentration of IL-6 secreted into the culture supernatant was determined by enzyme-linked immunosorbent assay(ELISA).Results:In KT cells, compared to the CONV group, FLASH irradiation resulted in a significantly higher survival fraction ( P<0.05), increased GRP78 protein expression ( t= 7.52, P < 0.05) and UPR-related genes PERK, ATF4, and CHOP. In A549, the cell survival rate did not differ significantly between the CONV and FLASH groups ( P > 0.05). UPR pathway was not activated in either group. However, both CONV and FLASH irradiation significantly promoted secretion of IL-6 ( t=4.31, 4.47, P<0.05), while no difference was identified between two groups. In KT, both irradiation promoted secretion of IL-6 ( t=7.43, 3.07, P<0.05) while IL-6 concentration in FLASH group was significantly lower than that in CONV group ( t=7.63, P<0.05). Additionally, a pro-apoptotic propensity in KT cells following FLASH irradiation and in A549 cells following both FLASH and CONV irradiation was identified. Conclusions:In KT cells, FLASH irradiation cleared misfolded proteins through activating UPR pathway, promoted apoptosis of damaged cells, suppressed IL-6 secretion to attenuate inflammatory injury, and ultimately enhanced cell survival. Furthermore, proton FLASH irradiation bypasses ER stress activation in A549 cells, instead directly priming an apoptotic disposition with concomitant IL-6 hypersecretion. This paracrine damage amplification cascade potentiates radiation-induced tumoricidal efficacy through sustained cytotoxic microenvironment remodeling.
