title: Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition.
abstract: Signal transducer and activator of transcription 3 (STAT3) has important roles in cancer aggressiveness and has been confirmed as an attractive target for cancer therapy. In this study, we used a dual-luciferase assay to identify that pectolinarigenin inhibited STAT3 activity. Further studies showed pectolinarigenin inhibited constitutive and interleukin-6-induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus and blocked STAT3 DNA-binding activity in osteosarcoma cells. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNA methyltransferase 1/HDAC1 histone deacetylase 1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma cell proliferation, induced apoptosis and reduced the level of STAT3 downstream proteins cyclin D1, Survivin, B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra-large (Bcl-xl) and myeloid cell leukemia 1 (Mcl-1). In addition, pectolinarigenin inhibited migration, invasion and reserved epithelial-mesenchymal transition (EMT) phenotype in osteosarcoma cells. In spontaneous and patient-derived xenograft models of osteosarcoma, we identified administration (intraperitoneal) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and impaired tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Suoyuan
authors.initials: S
authors.lastname: Li
authors.affiliation: The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingjie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhouying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Binhui
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zifei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chengqing
authors.initials: C
authors.lastname: Yi
authors.affiliation: Department of Orthopaedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Cai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology* / Q000633:toxicity; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology* / Q000633:toxicity; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000201:enzymology* / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D001688:Biological Products; D002867:Chromones; D050796:STAT3 Transcription Factor; C528671:pectolinarigenin; D019000:Phosphotyrosine; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6