Pectolinarigenin acts as a potential anti-osteosarcoma agent via mediating SHP-1/JAK2/STAT3 signaling

被引:12
|
作者
Zhang, Tao [1 ]
Li, Suoyuan [1 ,2 ]
Li, Jingjie [3 ]
Yin, Fei [1 ]
Hua, Yingqi [1 ]
Wang, Zhuoying [1 ]
Wang, Hongsheng [1 ]
Zuo, Dongqing [1 ]
Xu, Jing [1 ]
Cai, Zhengdong [1 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Shanghai Bone Tumor Inst, Dept Orthoped,Sch Med, Shanghai 200080, Peoples R China
[2] Suzhou Municipal Hosp, Suzhou, Peoples R China
[3] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Translat Med Ctr, Sch Med, Shanghai 200080, Peoples R China
关键词
Pectolinarigenin; Osteosarcoma; Metastasis; SHP-1; STAT3; signaling; TYROSINE-PHOSPHATASE SHP-1; HISTONE DEACETYLASE INHIBITOR; STAT3; ACTIVATION; HEPATOCELLULAR-CARCINOMA; MULTIPLE-MYELOMA; CANCER; APOPTOSIS; PATHWAY; GROWTH; GENE;
D O I
10.1016/j.biopha.2022.113323
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 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 growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed 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.
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页数:14
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