Identification and validation of p50 as the cellular target of eriocalyxin B
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Ling-Mei Kong1,2,‡, Xu Deng1,‡, Zhi-Li Zuo1, Han-Dong Sun1, Qin-Shi Zhao1,*, Yan Li1,*
1State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
2Graduate University of the Chinese Academy of Sciences, Beijing 100039, China
‡These authors contributed equally to this work
Yan Li, email: [email protected]
Qin-Shi Zhao, email: [email protected]
Keywords: EriB, activity-based probes, p50, NF-κB signaling, apoptosis
Received: June 24, 2014 Accepted: September 12, 2014 Published: October 24, 2014
As an ent-kaurene diterpenoid isolated from Isodon eriocalyx var. Laxiflora, Eriocalyxin B (EriB) possesses potent bioactivity of antitumor and anti-autoimmune inflammation, which has been suggested to work through inhibition of NF-kappaB (NF-κB) signaling. However, the direct target of EriB remains elusive. In this study, we showed that EriB induced apoptosis is associated with the inhibition of NF-κB signaling in SMMC-7721 hepatocellular carcinoma cells. With activity-based probe profiling, we identified p50 protein as the direct target of EriB. We showed that cysteine 62 is the critical residue of p50 for EriB binding through the α, β-unsaturated ketones. As the result, EriB selectively blocks the binding between p50 and the response elements, whereas having no effect on the dimerization or the nuclear translocation of p50 and p65. SiRNA mediated knockdown of p50 attenuated the apoptosis induced by EriB in SMMC-7721 cells. Taken together, our studies illustrated that EriB induces cancer cell apoptosis through interfering with the binding between NF-κB and the response elements by targeting the cysteine 62 of p50, which highlights its potential for the development of p50 targeted cancer therapeutic agents.
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