| Wang Xiaofei,Zhou Guangming,Hu Wentao.Differential endoplasmic reticulum stress signaling underlies the FLASH effect in human lung epithelial and lung cancer cells[J].Chinese Journal of Radiological Medicine and Protection,2025,45(11):1138-1143 |
| Differential endoplasmic reticulum stress signaling underlies the FLASH effect in human lung epithelial and lung cancer cells |
| Received:July 10, 2025 |
| DOI：10.3760/cma.j.cn112271-20250710-00242 |
| KeyWords:Proton FLASH irradiation Endoplasmic reticulum stress Lung epithelial cells Lung cancer cells |
| FundProject:国家自然科学基金(12475350) |
| Author Name | Affiliation | E-mail | | Wang Xiaofei | School of Radiation Medicine and Protection, State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education institutions, Suzhou Medical College of Soochow University, Suzhou 215123, China | | | Zhou Guangming | School of Radiation Medicine and Protection, State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education institutions, Suzhou Medical College of Soochow University, Suzhou 215123, China | | | Hu Wentao | School of Radiation Medicine and Protection, State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education institutions, Suzhou Medical College of Soochow University, Suzhou 215123, China | wthu@suda.edu.cn |
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| 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. |
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