Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer

炎症体 偶氮甲烷 粒体自噬 自噬 结肠炎 癌症研究 生物 下调和上调 半胱氨酸蛋白酶1 炎症 TXNIP公司 癌症 结直肠癌 药理学 免疫学 细胞生物学 生物化学 细胞凋亡 氧化应激 硫氧还蛋白 基因 遗传学
作者
Wenjie Guo,Yang Sun,Wen Li,Xingxin Wu,L. Guo,Peifen Cai,Xuefeng Wu,Xudong Wu,Yan Shen,Yongqian Shu,Yanhong Gu,Qiang Xu
出处
期刊:Autophagy [Informa]
卷期号:10 (6): 972-985 被引量:211
标识
DOI:10.4161/auto.28374
摘要

Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.
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