| 王笑菲,周光明,胡文涛.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[J].中华放射医学与防护杂志,2025,45(11):1138-1143.Wang Xiaofei,Zhou Guangming,Hu Wentao.Differential endoplasmic reticulum stress signaling underlies the FLASH effect in human lung epithelial and lung cancer cells[J].Chin J Radiol Med Prot,2025,45(11):1138-1143 |
| 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 |
| Differential endoplasmic reticulum stress signaling underlies the FLASH effect in human lung epithelial and lung cancer cells |
| 投稿时间：2025-07-10 |
| DOI：10.3760/cma.j.cn112271-20250710-00242 |
| 中文关键词: 质子FLASH 内质网应激 肺上皮细胞 肺癌细胞 |
| 英文关键词:Proton FLASH irradiation Endoplasmic reticulum stress Lung epithelial cells Lung cancer cells |
| 基金项目:国家自然科学基金(12475350) |
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| 中文摘要: |
| 目的 探究质子超高剂量率照射(FLASH)诱导肺上皮细胞与肺癌细胞内质网应激-凋亡通路响应的差异性及其生物学意义。方法 将人肺上皮细胞(KT)及肺癌细胞(A549)分别随机分为对照(Ctrl)组、常规剂量率(CONV)组和FLASH组进行质子照射。通过克隆存活实验绘制存活曲线。利用实时定量PCR和蛋白免疫印迹实验检测内质网应激及凋亡相关基因表达。应用酶联免疫吸附实验检测白介素6(IL-6)分泌。结果 FLASH照射后KT细胞存活率相比CONV组更高(P＜0.05), 葡萄糖调节蛋白78(GRP78)蛋白表达增多(t=7.52, P＜0.05), UPR相关基因PERK、ATF4、CHOP的mRNA水平升高且与蛋白表达一致;A549细胞CONV组与FLASH组间存活率差异无统计学意义(P>0.05)且UPR通路均未激活, IL-6分泌均较Ctrl组增多(t=4.31、4.47, P＜0.05), 且两组间差异无统计学意义(P>0.05)。KT中两组IL-6分泌也增多(t=7.43、3.07, P＜0.05), 但FLASH组分泌显著低于CONV组(t=7.63, P＜0.05)。KT细胞仅FLASH组趋于促凋亡, 而A549细胞两组均趋于促凋亡。结论 FLASH照射KT细胞通过激活UPR清除错误折叠蛋白, 促进损伤细胞凋亡, 并抑制IL-6分泌, 以减轻炎性损伤促进细胞存活。相反, FLASH照射A549细胞未诱发内质网应激, 细胞趋于凋亡且IL-6分泌增加, 并重塑细胞毒性微环境, 增强了辐射诱导的肿瘤杀伤效力。 |
| 英文摘要: |
| 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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