Eudesmane-Type Sesquiterpene Lactones Inhibit Nuclear Translocation of the Nuclear Factor κB Subunit RelB in Response to a Lymphotoxin β Stimulation

Abstract

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.Key words eudesmane; lymphotoxin β; nuclear factor κB; RelB; sesquiterpene lactone Nuclear factor κB (NF-κB) is a family of structurally-related eukaryotic transcription factors that regulate the expression of a number of important genes, including those related to cell proliferation, cell death, and inflammation.1) The NF-κB family consists of five subunits: RelA(p65), RelB, c-Rel, p105/p50, and p100/p52. 2)Various types of stimuli, including inflammatory cytokines, activate the canonical and non-canonical NF-κB signaling pathways.3) In the canonical NF-κB pathway, tumor necrosis factor (TNF) family members, such as TNF-α, induce the activation of the inhibitor of NF-κB (IκB) kinase β. 4) In the cytosol, IκB sequesters the NF-κB heterodimers RelA and p50 and prevents their nuclear translocation. 4) Upon phosphorylation, IκB undergoes ubiquitination and proteasomal degradation, leading to the liberation and nuclear translocation of the RelA and p50 heterodimers. 5) In contrast, the non-canonical NF-κB pathway is triggered by other TNF family members, such as lymphotoxin β (LTβ).6) The NF-κB subunits RelB and p100/p52 play essential roles in the non-canonical NF-κB pathway. 7) In unstimulated cells, p100 constitutively associates with RelB in the cytosol and inhibits its activity.7) Upon a stimulation with LTβ, IκB kinase α is primarily activated and then directly phosphorylates p100.3) Phosphorylated p100 is ubiquitinated and processed into p52 by proteasome, leading to the nuclear ...

Research Advances on Health Effects of Edible Artemisia Species and Some Sesquiterpene Lactones Constituents

“…In vitro results are much more abundant for santonin derivatives, mainly detailing the synthesis of novel cancer therapeutic agents. Santonin tumor inhibitory derivatives have included a diacetoxy acetal form [262]; spiro-isoxazoline and spiro-isoxazolidine derivatives [263,264]; cinnamic acid derivatives [265], immunosuppressants [266]; anti-inflammatory bromoketone [267][268][269]. Given the scope of the previously cited reviews, here it will be highlighting the main recently published derivatives showing potent in vivo effects.…”