Wedelolactone, a Naturally Occurring Coumestan, Enhances Interferon-γ Signaling through Inhibiting STAT1 Protein Dephosphorylation

Signal transducers and activators of transcription 1 (STAT1) transduces signals from cytokines and growth factors, particularly IFN-gamma, and regulates expression of genes involved in cell survival/death, proliferation, and migration. STAT1 is activated through phosphorylation on its tyrosine 701 by JAKs and is inactivated through dephosphorylation by tyrosine phosphatases. We discovered a natural compound, wedelolactone, that increased IFN-gamma signaling by inhibiting STAT1 dephosphorylation and prolonging STAT1 activation through specific inhibition of T-cell protein tyrosine phosphatase (TCPTP), an important tyrosine phosphatase for STAT1 dephosphorylation. More interestingly, wedelolactone inhibited TCPTP through interaction with the C-terminal autoinhibition domain of TCPTP. We also found that wedelolactone synergized with IFN-gamma to induce apoptosis of tumor cells. Our data suggest a new target for anticancer or antiproliferation drugs, a new mechanism to regulate PTPs specifically, and a new drug candidate for treating cancer or other proliferation disorders.