2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.
Bottom Line: The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively.We have identified 2-methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK. 2-MS inhibits both interleukin-6-induced and constitutively-activated STAT3, as well as tumor necrosis factor-α-induced NF-κB activation. 2-MS specifically inhibits JAK and IKKβ kinase activities but has little effect on activities of other kinases tested.We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-κB pathways, is a promising anticancer drug candidate.
Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.Show MeSH
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Mentions: We screened an extract library of Chinese medicinal herbs for their inhibitory effect on STAT3 signaling using a STAT3 responsive luciferase reporter gene-transfected HepG2 cell line and found 2-MS (Fig. 1), which inhibited STAT3 activity in both a luciferase assay using the HepG2 cells and a western blotting assay using MDA-MB-231 cells.(21) To confirm the inhibitory effects of 2-MS on the JAK2/STAT3 signaling pathway, we examined its effects on the IL-6-induced phosphorylation/activation of STAT3. 2-MS inhibited both the IL-6-induced and the constitutive phosphorylation/activation of STAT3 in a dose-dependent manner in HeLa cells (Fig. 2a,c). The inhibition was rapid. A 15-min treatment was sufficient to block the activation (Fig. 2b), suggesting direct inhibition of the STAT3 phosphorylation. 2-MS also significantly inhibited the constitutive activation of STAT3 in MCF-7, DU-145 and HepG2 cells (Fig. 2d). Therefore, 2-MS inhibited both the IL-6 induced as well as the constitutive activation of STAT3 in human tumor cells.
Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.