2022年8月1日,复旦大学放射医学研究所邵春林教授团队在《Autophagy》上在线发表了题为“SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes...2022年8月1日,复旦大学放射医学研究所邵春林教授团队在《Autophagy》上在线发表了题为“SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes”的研究论文,该研究揭示了胶质母细胞瘤中转谷氨酰胺酶TGM2通过多配体聚糖SDC1依赖的方式转运至溶酶体,促进束缚因子EPG5介导的自噬体-溶酶体融合,最终增强肿瘤的辐射抵抗,为胶质母细胞瘤放疗提供新的潜在增敏靶点。展开更多
AIM To investigate the mechanism of chaperone-mediated autophagy(CMA)-induced resistance to irradiationtriggered apoptosis through regulation of the p53 protein in hepatocellular carcinoma(HCC). METHODS Firstly, we de...AIM To investigate the mechanism of chaperone-mediated autophagy(CMA)-induced resistance to irradiationtriggered apoptosis through regulation of the p53 protein in hepatocellular carcinoma(HCC). METHODS Firstly, we detected expression of lysosome-associated membrane protein 2a(Lamp-2a), which is the key protein of CMA, by western blot in Hep G2 and SMMC7721 cells after irradiation. We further used sh RNA Lamp-2a HCC cells to verify the radioresistance induced by CMA. Next, we detected the HMGB1 and p53 expression after irradiation by western blot, and we further used RNA interference and ethyl pyruvate(EP), as a HMGB1 inhibitor, to observe changes of p53 expression. Finally, an immunoprecipitation assay was conducted to explore the interaction between Lamp-2a and HMGB1, and the data were analyzed. RESULTS We found the expression of Lamp-2a was increased on irradiation while apoptosis decreased in Hep G2 and SMMC7721 cells. The apoptosis was increased markedly in the sh RNA Lamp-2a Hep G2 and SMMC7721 cells as detected by western blot and colony formation assay. Next, we found p53 expression was gradually reduced on irradiation but obviously increased in sh RNA Lamp-2a cells. Furthermore, p53 increased the cell apoptosis on irradiation in Hep3B(p53-/-) cells. Finally, p53 levels were regulated by HMGB1 as measured through RNA interference and the EP treatment. HMGB1 was able to combine with Lamp-2a as seen by immunoprecipitation assay and was degraded via the CMA pathway. The decreased HMGB1 inhibited p53 expression induced by irradiation and further reduced the apoptosis in HCC cells. CONCLUSION CMA pathway activation appears to down-regulate the susceptibility of HCC to irradiation by degrading HMGB1 with further impact on p53 expression. These findings have clinical relevance for radiotherapy of HCC.展开更多
文摘2022年8月1日,复旦大学放射医学研究所邵春林教授团队在《Autophagy》上在线发表了题为“SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes”的研究论文,该研究揭示了胶质母细胞瘤中转谷氨酰胺酶TGM2通过多配体聚糖SDC1依赖的方式转运至溶酶体,促进束缚因子EPG5介导的自噬体-溶酶体融合,最终增强肿瘤的辐射抵抗,为胶质母细胞瘤放疗提供新的潜在增敏靶点。
基金Supported by Natural Science Foundation of Hebei Province,China,No.H2016209007
文摘AIM To investigate the mechanism of chaperone-mediated autophagy(CMA)-induced resistance to irradiationtriggered apoptosis through regulation of the p53 protein in hepatocellular carcinoma(HCC). METHODS Firstly, we detected expression of lysosome-associated membrane protein 2a(Lamp-2a), which is the key protein of CMA, by western blot in Hep G2 and SMMC7721 cells after irradiation. We further used sh RNA Lamp-2a HCC cells to verify the radioresistance induced by CMA. Next, we detected the HMGB1 and p53 expression after irradiation by western blot, and we further used RNA interference and ethyl pyruvate(EP), as a HMGB1 inhibitor, to observe changes of p53 expression. Finally, an immunoprecipitation assay was conducted to explore the interaction between Lamp-2a and HMGB1, and the data were analyzed. RESULTS We found the expression of Lamp-2a was increased on irradiation while apoptosis decreased in Hep G2 and SMMC7721 cells. The apoptosis was increased markedly in the sh RNA Lamp-2a Hep G2 and SMMC7721 cells as detected by western blot and colony formation assay. Next, we found p53 expression was gradually reduced on irradiation but obviously increased in sh RNA Lamp-2a cells. Furthermore, p53 increased the cell apoptosis on irradiation in Hep3B(p53-/-) cells. Finally, p53 levels were regulated by HMGB1 as measured through RNA interference and the EP treatment. HMGB1 was able to combine with Lamp-2a as seen by immunoprecipitation assay and was degraded via the CMA pathway. The decreased HMGB1 inhibited p53 expression induced by irradiation and further reduced the apoptosis in HCC cells. CONCLUSION CMA pathway activation appears to down-regulate the susceptibility of HCC to irradiation by degrading HMGB1 with further impact on p53 expression. These findings have clinical relevance for radiotherapy of HCC.
