School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P. R. China.
Guangzhou First People's Hospital, School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou, Guangdong 510006, P. R. China.
Am J Chin Med. 2020;48(8):1915-1940. doi: 10.1142/S0192415X20500962. Epub 2020 Dec 10.
Autophagy is an important tightly controlled cellular process that regulates cellular homeostasis and is involved in deciding cell fate such as cell survival and death. The role of autophagy in many intracellular signaling pathways explains its interaction with other different types of cell death, including apoptosis and immunogenic cell death (ICD). The reports showed the complex and intriguing relationship existing between autophagy and immune system signaling pathways. However, the role of autophagy in ICD remains to be clearly elucidated. In this study, we demonstrated that Brucine, a clinically-used small molecule in traditional Chinese medicine, elicited autophagy inhibition. Brucine also triggered cell stress and induced features of ICD, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release in MDA-MB-231 and CT26 cancer cells. Brucine impaired autolysosomal degradation and exerted a feedback regulation of ERK1/2-mTOR-p70S6K signaling cascade. Brucine-elicited ICD was confirmed by the rejection of CT26 tumor cells, implanted in the mice after vaccination with Brucine-treated CT26 cells. The impaired autophagy contributed to Brucine-induced ICD, as knock-down of Atg5 significantly reduced Brucine-elicited CRT exposure and HMGB1 release. Our results revealed Brucine as a novel autophagy regulator, ICD inducer and hitherto undocumented role of autophagy in ICD. Thus, these results imply the importance of Brucine in cancer immunotherapy. Therefore, Brucine may be used as an ICD inducer and improve its application in cancer treatment with minimized toxicity.
自噬是一种重要的、受到严格调控的细胞过程，它可以调节细胞内稳态，并参与决定细胞命运，如细胞存活和死亡。自噬在许多细胞内信号通路中的作用解释了它与其他不同类型的细胞死亡（包括细胞凋亡和免疫原性细胞死亡（ICD））的相互作用。报告显示，自噬与免疫系统信号通路之间存在着复杂而有趣的关系。然而，自噬在 ICD 中的作用仍有待阐明。在本研究中，我们证明了临床使用的中药小分子马钱子碱能抑制自噬。马钱子碱还能引发细胞应激，并诱导 MDA-MB-231 和 CT26 癌细胞产生 ICD 的特征，包括钙网织蛋白（CRT）暴露和高迁移率族蛋白 1（HMGB1）释放。马钱子碱损害自噬溶酶体降解，并对 ERK1/2-mTOR-p70S6K 信号级联产生反馈调节。马钱子碱诱导的 ICD 被植入经马钱子碱处理的 CT26 细胞接种疫苗的小鼠中的 CT26 肿瘤细胞排斥所证实。自噬的损害有助于马钱子碱诱导的 ICD，因为 Atg5 的敲低显著减少了马钱子碱诱导的 CRT 暴露和 HMGB1 释放。我们的结果揭示了马钱子碱作为一种新型自噬调节剂、ICD 诱导剂和自噬在 ICD 中的迄今未被记录的作用。因此，这些结果表明马钱子碱在癌症免疫治疗中的重要性。因此，马钱子碱可以作为 ICD 诱导剂，并在癌症治疗中最小化毒性来改善其应用。
