title: Wedelolactone, a naturally occurring coumestan, enhances interferon-γ signaling through inhibiting STAT1 protein dephosphorylation.
abstract: Signal transducers and activators of transcription 1 (STAT1) transduces signals from cytokines and growth factors, particularly IFN-γ, 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-γ 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-γ 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.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Shensi
authors.initials: S
authors.lastname: Shen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Haohao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China. Electronic address: qyu@sibs.ac.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003374:Coumarins / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D010936:Plant Extracts; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C051122:wedelolactone; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; C505898:coumestan
keywords: Cytokines/Interferon; Phosphatase; STAT Transcription Factor; Tumor Suppressor Gene; Tumor Therapy