Arctigenin disrupts NLRP3 inflammasome assembly in colonic macrophages via downregulating fatty acid oxidation to prevent colitis-associated cancer

Copyright © 2020 Elsevier B.V. All rights reserved..

Arctigenin, the major active constituent of Fructus Arctii, has been reported to inhibit the growth of various tumors and alleviate colitis. This study aimed to prove the protective effect of arctigenin on colitis-associated cancer (CAC) and explore its mechanisms. Orally administered arctigenin prevented the progression of colitis and protected against colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC mice. Arctigenin downregulated NLRP3 inflammasome activation and fatty acid oxidation (FAO) metabolism in macrophages, as determined by untargeted metabolomics. Arctigenin also inhibited the expression of carnitine palmitoyltransferase 1 (CPT1), reduced the acetylation of α-tubulin, and disrupted NLRP3 complex formation, which in turn inactivated the NLRP3 inflammasome. Downregulation of the CPT1-FAO-acetyl-coenzyme A (acetyl-CoA)-acetylated α-tubulin pathway was observed to inhibit the effect of arctigenin on NLRP3 inflammasome assembly, as confirmed by CPT1 overexpression. Lastly, arctigenin was shown to inhibit NLRP3 inflammasome activation and improve CAC in mice, and the effect was significantly diminished by the overexpression of adeno-associated virus (AAV)9-CPT1. Taken together, these results show that the inhibition of NLRP3 inflammasome assembly in macrophages due to FAO downregulation contributes to the preventative effect of arctigenin against CAC. Our findings highlight the potential value of arctigenin to reduce the risk of CAC in patients with colitis.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:491

Enthalten in:

Cancer letters - 491(2020) vom: 28. Okt., Seite 162-179

Sprache:

Englisch

Beteiligte Personen:

Qiao, Simiao [VerfasserIn]
Lv, Changjun [VerfasserIn]
Tao, Yu [VerfasserIn]
Miao, Yumeng [VerfasserIn]
Zhu, Yanrong [VerfasserIn]
Zhang, Wenjie [VerfasserIn]
Sun, Dandan [VerfasserIn]
Yun, Xinming [VerfasserIn]
Xia, Yufeng [VerfasserIn]
Wei, Zhifeng [VerfasserIn]
Dai, Yue [VerfasserIn]

Links:

Volltext

Themen:

Arctigenin
Carnitine O-Palmitoyltransferase
Carnitine palmitoyltransferase 1
Colitis-associated cancer
EC 2.3.1.21
Fatty Acids
Fatty acid oxidation
Furans
Inflammasomes
Interleukin-1beta
Journal Article
Lignans
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 inflammasome
Research Support, Non-U.S. Gov't
U76MR9VS6M

Anmerkungen:

Date Completed 22.02.2021

Date Revised 22.02.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.canlet.2020.08.033

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM314348476