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: The inhibitory effect of 2-MS on STAT3 activation suggested that 2-MS might interfere with the upstream components of the STAT3 signaling pathway. Because JAK2 is the major kinase to activate STAT3 while GP130 is important for tyrosine phosphorylation of JAK2 in the IL-6/STAT3 pathway,(22) we first analyzed the effects of 2-MS on the expression and phosphorylation of JAK2 and the expression of GP130. In HeLa cells, 10 μM 2-MS significantly inhibited phosphorylation of JAK2 (Y1007/1008), while it had no effects on the expressions of JAK2 and GP130 (Fig. 3a). In addition, 10 μM 2-MS significantly inhibited the phosphorylation of JAK2 (Y1007/1008) in HeLa cells without IL-6 stimulation, further suggesting that JAK2 is the direct target of 2-MS (Fig. 3b).
Affiliation: Division of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.