Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Cancer Lett. 2020 Oct 28;491:162-179. doi: 10.1016/j.canlet.2020.08.033. Epub 2020 Aug 27.
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.
牛蒡子苷元是牛蒡子的主要活性成分，据报道其可抑制多种肿瘤的生长并缓解结肠炎。本研究旨在证明牛蒡子苷元对结肠炎相关癌症（CAC）的保护作用，并探讨其机制。口服牛蒡子苷元可防止结肠炎的进展，并防止氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的 CAC 小鼠发生结肠癌。通过非靶向代谢组学研究发现，牛蒡子苷元可下调巨噬细胞中 NLRP3 炎性小体的激活和脂肪酸氧化（FAO）代谢。牛蒡子苷元还抑制肉碱棕榈酰转移酶 1（CPT1）的表达，减少α-微管蛋白的乙酰化，并破坏 NLRP3 复合物的形成，从而使 NLRP3 炎性小体失活。下调 CPT1-FAO-乙酰辅酶 A（acetyl-CoA）-乙酰化α-微管蛋白途径可抑制牛蒡子苷元对 NLRP3 炎性小体组装的作用，这一点通过 CPT1 过表达得到了证实。最后，牛蒡子苷元可抑制 NLRP3 炎性小体的激活并改善 CAC 小鼠的病情，而过表达腺相关病毒（AAV）9-CPT1 则显著减弱了其作用。综上所述，这些结果表明，由于 FAO 下调导致巨噬细胞中 NLRP3 炎性小体组装受到抑制，这有助于牛蒡子苷元预防 CAC 的作用。我们的研究结果突出了牛蒡子苷元降低结肠炎患者 CAC 风险的潜在价值。
