Inteferon γ (IFN-γ) is a cytokine that plays important roles in promoting innate and adaptive immune responses, as well as in preventing development of primary and transplanted tumors. IFN-γ can control tumor development through the host immune system. It can also regulate downstream STAT1 (signal transducers and activators of transcription 1) responded genes in tumor cells that have anti-tumor functions. Loss of STAT1 signaling has been found in a large group of diverse tumors.
Research group lead by Prof. YU Qiang in Shanghai Institute of Materia Medica (SIMM) identified Wedelolactone, a coumestan isolated from Eclipta prostrate L., as an enhancer of IFN-γ-induced STAT1 signaling through screening of a natural compound library.
Wedelolactone synergistically enhanced IFN-γ-induced apoptosis of tumor cells in a STAT1-dependent manner. The studies showed that Wedelolactone did not affect the binding of IFN-γ to its receptor. Instead, it enhanced IFN-γ/STAT1 signaling by prolonging STAT1 tyrosine phosphorylation. Interestingly, the compound specifically enhanced IFN-γsignaling, and had no effects on IFN-α, IL-6 or EGF signaling.
Further mechanism studies showed that Wedelolactone increased IFN-γ signaling by inhibiting STAT1 dephosphorylation 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. Efforts have been made to develop drugs against PTPs, since they are linked to several diseases and therefore their regulators may serve as therapeutic agents. But the highly conserved architectures of PTP active sites impede the development of selective PTP inhibitors.
The research of Wedelolectone suggests a new mechanism to regulate PTPs specifically. Meanwhile, the authors identified a novel antitumor drug candidate and a new target for anticancer or antiproliferation drugs. This work has been formally published on the Journal of Biological Chemistry (May 17, 2013, 288: 14417-14427).
This work was supported by the China Ministry of Science & Technology “Key New Drug Creation and Manufacturing Program”, the China Ministry of Science and Technology Research Grant, the China National Natural Science Foundation Grants, and the National Science and Technology 973 grants.
Full text: http://www.jbc.org/content/288/20/14417.full#F1

(Source of News: YU Qiang ’s group)