Vu Quy Van, Sayama Shinsei, Ando Masayoshi, Kataoka Takao
Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Department of Natural Sciences (Chemistry), Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Molecules. 2024 Apr 19;29(8):1866. doi: 10.3390/molecules29081866.
Alantolactone is a eudesmane-type sesquiterpene lactone containing an α-methylene-γ-lactone moiety. Previous studies showed that alantolactone inhibits the nuclear factor κB (NF-κB) signaling pathway by targeting the inhibitor of NF-κB (IκB) kinase. However, in the present study, we demonstrated that alantolactone selectively down-regulated the expression of tumor necrosis factor (TNF) receptor 1 (TNF-R1) in human lung adenocarcinoma A549 cells. Alantolactone did not affect the expression of three adaptor proteins recruited to TNF-R1. The down-regulation of TNF-R1 expression by alantolactone was suppressed by an inhibitor of TNF-α-converting enzyme. Alantolactone increased the soluble forms of TNF-R1 that were released into the culture medium as an ectodomain. The structure-activity relationship of eight eudesmane derivatives revealed that an α-methylene-γ-lactone moiety was needed to promote TNF-R1 ectodomain shedding. In addition, parthenolide and costunolide, two sesquiterpene lactones with an α-methylene-γ-lactone moiety, increased the amount of soluble TNF-R1. Therefore, the present results demonstrate that sesquiterpene lactones with an α-methylene-γ-lactone moiety can down-regulate the expression of TNF-R1 by promoting its ectodomain shedding in A549 cells.
土木香内酯是一种桉叶烷型倍半萜内酯，含有一个α-亚甲基-γ-内酯部分。先前的研究表明，土木香内酯通过靶向核因子κB（NF-κB）抑制剂（IκB）激酶来抑制NF-κB信号通路。然而，在本研究中，我们证明了土木香内酯在人肺腺癌A549细胞中选择性地下调肿瘤坏死因子（TNF）受体1（TNF-R1）的表达。土木香内酯不影响募集到TNF-R1的三种衔接蛋白的表达。土木香内酯对TNF-R1表达的下调被TNF-α转换酶抑制剂所抑制。土木香内酯增加了作为胞外域释放到培养基中的可溶性TNF-R1的形式。八种桉叶烷衍生物的构效关系表明，需要α-亚甲基-γ-内酯部分来促进TNF-R1胞外域的脱落。此外，另外两种含有α-亚甲基-γ-内酯部分的倍半萜内酯——小白菊内酯和木香烃内酯，增加了可溶性TNF-R1的量。因此，本研究结果表明，含有α-亚甲基-γ-内酯部分的倍半萜内酯可以通过促进其在A549细胞中的胞外域脱落来下调TNF-R1的表达。
