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Mitophagy‐mediated NLRP3 inflammasome inhibition by andrographolide contributes to the prevention of colitis‐associated cancer (1052.3)
Author(s) -
Sun Yang,
Guo Wenjie,
Xu Qiang
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1052.3
Subject(s) - andrographolide , inflammasome , mitophagy , autophagy , pharmacology , andrographis paniculata , azoxymethane , chemistry , cancer research , pi3k/akt/mtor pathway , inflammation , medicine , cancer , immunology , biochemistry , signal transduction , apoptosis , colorectal cancer , alternative medicine , pathology
Intestinal nonresolving inflammation predisposes to the development of colitis‐associated cancer (CAC). Inflammasomes are believed to mediate intestine homeostasis, and their dysregulation contribute to inflammatory diseases and CAC. However, few agent capable of targeting inflammasomes to reduce CAC has been reported thus far. Here we report that small molecule andrographolide protects mice against CAC in the mouse model of azoxymethane combination of dextran sulfate sodium through inhibiting NLRP3 inflammasome. Oral administration of andrographolide significantly attenuated the colitis progression and tumors burden, which was accompanied by lessened body weight loss, lower disease activity index, decreased expression of cyclooxygenase‐2 and proinflammatory cytokines, lower activation of NF‐κB and STAT3, as well as reduced cell proliferation and angiogenesis in the colons of CAC mice. Further study showed that andrographolide inhibited NLRP3 inflammasome activation in macrophage in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3/PYCARD/CASP1 complex assembly and lower IL‐1β secretion. Moreover, andrographolide was found to trigger mitophagy in macrophage, leading to the less mitochondrial membrane potential collapse, and this in turn inactivated the NLRP3 inflammasome. Furthermore, inhibition of the PIK3CA‐AKT1‐MTOR‐RPS6KB1 pathway accounted for the induction of autophagy by andrographolide. Finally, andrographolide‐induced inhibition of IL‐1β production was blocked by the knockdown of BECN1 expression, or by autophagy inhibitor 3‐methyladenine. Taken together, our findings demonstrate that andrographolide‐driven mitophagy‐mediated NLRP3 inflammasome inhibition is responsible for the prevention of CAC. Our data may help to guide decisions regarding the use of andrographolide in colitis patients, which ultimately reduces the risk of CAC. Grant Funding Source : supported by NSFC of China (Nos. 91229109, 90913023, 81121062, 91129728 and 81273528)