3′-epi-12β-hydroxyfroside-mediated autophagy degradation of RIPK1/RIPK3 necrosomes leads to anergy of immunogenic cell death in triple-negative breast cancer cells
3′-epi-12β-hydroxyfroside-mediated autophagy degradation of RIPK1/RIPK3 necrosomes leads to anergy of immunogenic cell death in triple-negative breast cancer cells
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3α-epi-12β-羟基froside 介导的 RIPK1/RIPK3 坏死体的自噬降解导致三阴性乳腺癌细胞免疫原性细胞死亡的无反应性
DOI：
10.1016/j.phrs.2022.106613
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发表时间：
2022-12-19
影响因子：
9.3
通讯作者：
Zheng, Wu-Ping
中科院分区：
文献类型：
--
作者：
Huang, Feng-Ying;Dai, Shu-Zhen;Zheng, Wu-Ping
越来越多的研究表明，一些强心苷，如传统的地高辛（DIG）和洋地黄毒苷，可以诱导各种肿瘤的免疫原性细胞死亡（ICD）。我们以前发现，3 '-epi-12 β-hydroxyfroside（HyFS），一种由我们小组分离的新的Cardenoprotein化合物，可以通过失活Akt/mTOR通路诱导细胞保护性自噬。然而，HyFS是否能诱导ICD仍不清楚。在这项研究中，我们将我们的工作扩展到进一步研究HyFS是否可以诱导自噬和ICD，我们研究了自噬和ICD之间的关系，在三个TNBC细胞系。出乎意料的是，与DIG相比，我们发现HyFS可以在三种人三阴性乳腺癌（TNBC）细胞系和一种鼠TNBC模型中诱导完全的自噬通量，但不能诱导ICD。HyFS诱导的自噬的抑制导致TNBC MDA-MB-231、MDA-MB-436和HCC 38细胞中ICD的产生。进一步的机制研究表明，RIPK1/RIPK3坏死体的形成是DIG处理的TNBC细胞中ICD诱导所必需的，而HyFS处理通过自噬过程导致受体相互作用丝氨酸-苏氨酸激酶（RIPK）1/3坏死体降解。此外，自噬抑制剂氯喹对HyFS诱导的自噬的抑制导致ICD的复发和肿瘤微环境的逆转，导致免疫活性小鼠比免疫缺陷小鼠具有更显著的抗肿瘤作用。这些发现表明，HyFS介导的RIPK1/RIPK3坏死体的自噬降解导致TNBC细胞中ICD的失活。此外，HyFS和自噬抑制剂的联合治疗可增强抗肿瘤活性，提示TNBC治疗的替代治疗。
Increasing studies have suggested that some cardiac glycosides, such as conventional digoxin (DIG) and digitoxin, can induce immunogenic cell death (ICD) in various tumors. We previously found that 3 '-epi-12 beta-hydroxyfroside (HyFS), a novel cardenolide compound isolated by our group, could induce cytoprotective autophagy through inactivation of the Akt/mTOR pathway. However, whether HyFS can induce ICD remains unknown. In this study, we extend our work to further investigate whether HyFS could induce both autophagy and ICD, and we investigated the relationship between autophagy and ICD in three TNBC cell lines. Unexpectedly, compared to DIG, we found that HyFS could induce complete autophagy flux but not ICD in three human triple-negative breast cancer (TNBC) cell lines and one murine TNBC model. Inhibition of HyFS-induced autophagy resulted in the production of ICD in TNBC MDA-MB-231, MDA-MB-436, and HCC38 cells. A further mechanism study showed that formation of RIPK1/RIPK3 necrosomes was necessary for ICD induction in DIG treated TNBC cells, while HyFS treatment led to receptor-interacting serine-threonine kinase (RIPK)1/3 necrosome degradation via an autophagy process. Additionally, inhibition of HyFS-induced autophagy by the autophagy inhibitor chloroquine resulted in the reoccurrence of ICD and reversion of the tumor microenvironment, leading to more significant antitumor effects in immunocompetent mice than in immunodeficient mice. These findings indicate that HyFS-mediated autophagic degradation of RIPK1/RIPK3 necrosomes leads to inactivation of ICD in TNBC cells. Moreover, combined treatment with HyFS and an autophagy inhibitor may enhance the antitumor activities, suggesting an alternative therapeutic for TNBC treatment.