Quach Hue Tu, Kondo Tetsuya, Watanabe Megumi, Tamura Ryuichi, Yajima Yoshiki, Sayama Shinsei, Ando Masayoshi, Kataoka Takao
Department of Applied Biology, Kyoto Institute of Technology.
Department of Natural Sciences (Chemistry), Fukushima Medical University.
Biol Pharm Bull. 2017;40(10):1669-1677. doi: 10.1248/bpb.b17-00170.
The transcription factor nuclear factor κB (NF-κB) regulates various biological processes, including inflammatory responses. We previously reported that eudesmane-type sesquiterpene lactones inhibited multiple steps in the canonical NF-κB signaling pathway induced by tumor necrosis factor-α and interleukin-1α. In contrast, the biological activities of eudesmane-type sesquiterpene lactones on the non-canonical NF-κB signaling pathway remain unclear. In the present study, we found that (11S)-2α-bromo-3-oxoeudesmano-12,6α-lactone, designated santonin-related compound 2 (SRC2), inhibited NF-κB luciferase reporter activity induced by lymphotoxin β (LTβ) in human lung carcinoma A549 cells. Although SRC2 did not prevent the processing of the NF-κB subunit p100 induced by LTβ, it inhibited the nuclear translocation of RelB and p52 in response to the LTβ stimulation. In contrast to (-)-dehydroxymethylepoxyquinomicin, SRC2 inhibited the LTβ-induced nuclear translocation of the RelB (C144S) mutant in a manner similar to wild-type RelB. While eudesmane derivatives possessing an α-bromoketone moiety or α,β-unsaturated carbonyl moieties inhibited LTβ-induced NF-κB luciferase reporter activity, eudesmane derivatives possessing an α-bromoketone moiety exhibited stronger inhibitory activity on the LTβ-induced nuclear translocation of RelB than those possessing a single α-methylene-γ-lactone moiety. The results of the present study revealed that SRC2 inhibits the nuclear translocation of RelB in the non-canonical NF-κB signaling pathway induced by LTβ.
转录因子核因子κB（NF-κB）调节包括炎症反应在内的多种生物学过程。我们之前报道过桉叶烷型倍半萜内酯可抑制肿瘤坏死因子-α和白细胞介素-1α诱导的经典NF-κB信号通路中的多个步骤。相比之下，桉叶烷型倍半萜内酯对非经典NF-κB信号通路的生物学活性仍不清楚。在本研究中，我们发现（11S）-2α-溴-3-氧代桉叶烷-12,6α-内酯，命名为山道年相关化合物2（SRC2），可抑制人肺癌A549细胞中淋巴毒素β（LTβ）诱导的NF-κB荧光素酶报告基因活性。虽然SRC2不能阻止LTβ诱导的NF-κB亚基p100的加工过程，但它可抑制RelB和p52响应LTβ刺激后的核转位。与（-）-去氢甲基环氧喹霉素不同，SRC2以类似于野生型RelB的方式抑制LTβ诱导的RelB（C144S）突变体的核转位。虽然含有α-溴代酮部分或α,β-不饱和羰基部分的桉叶烷衍生物可抑制LTβ诱导的NF-κB荧光素酶报告基因活性，但含有α-溴代酮部分的桉叶烷衍生物对LTβ诱导的RelB核转位的抑制活性比含有单个α-亚甲基-γ-内酯部分的衍生物更强。本研究结果表明，SRC2可抑制LTβ诱导的非经典NF-κB信号通路中RelB的核转位。
