School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
Mycology and Biotechnology group, Plant, Agroscope, Route de Duillier 60, P.O. Box 1012, 1260 Nyon, Switzerland.
Molecules. 2018 Mar 12;23(3):636. doi: 10.3390/molecules23030636.
Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of , a fungus that grows naturally on dung. was cultivated in Potato Dextrose Broth and extracted with ethyl acetate. Bioassay-guided fractionation of this extract was performed by measuring NF-κB activity using a HEK293 cell line transfected with an NF-κB-driven luciferase reporter gene. The mycotoxin patulin was identified as a nanomolar inhibitor of TNF-α-induced NF-κB activity. Immunocytochemistry and Western blot analyses revealed that its mechanism of action involved an inhibition of p65 nuclear translocation and was independent from the NF-κB inhibitor α (IκBα) degradation process. Enhancing its interest in lung cancer chemoprevention, patulin also exhibited antiproliferative, proapoptotic, and antimigration effects on human lung adenocarcinoma cells through inhibition of the Wnt pathway.
肺癌是世界上最致命的癌症形式。它的发展通常涉及核因子 kappa B（NF-κB）途径的过度激活，导致细胞增殖、存活、迁移增加，凋亡减少。因此，NF-κB 抑制剂被积极用于癌症的化学预防和治疗，而真菌则代表了这种分子的一个有趣的未被探索的来源。本工作的目的是通过研究自然生长在粪便上的真菌的代谢产物，寻找天然存在的肺癌化学预防化合物。在马铃薯葡萄糖肉汤中培养，并使用乙酸乙酯提取。通过使用转染 NF-κB 驱动的荧光素酶报告基因的 HEK293 细胞系测量 NF-κB 活性，对该提取物进行基于生物测定的分级分离。发现真菌毒素棒曲霉素是 TNF-α 诱导的 NF-κB 活性的纳摩尔抑制剂。免疫细胞化学和 Western blot 分析表明，其作用机制涉及抑制 p65 核易位，并且不依赖于 NF-κB 抑制剂α（IκBα）降解过程。棒曲霉素通过抑制 Wnt 途径对人肺腺癌细胞表现出增殖抑制、促凋亡和抗迁移作用，增强了其在肺癌化学预防中的应用。
