Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated tha...Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 （G-Rg5） and Rkl （G-Rkl）, with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rkl inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two gin- senosides decreased the expression of inhibitor of apoptosis proteins （lAPs）, leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rkl, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rkl. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rkl on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demon- strated that G-Rg5 and G-Rkl inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rkl might be promising natural compounds for targeted cancer therapy.展开更多
文摘Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 （G-Rg5） and Rkl （G-Rkl）, with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rkl inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two gin- senosides decreased the expression of inhibitor of apoptosis proteins （lAPs）, leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rkl, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rkl. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rkl on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demon- strated that G-Rg5 and G-Rkl inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rkl might be promising natural compounds for targeted cancer therapy.
