Natural Product Pectolinarigenin Inhibits Osteosarcoma Growth and Metastasis Via SHP-1-mediated STAT3 Signaling Inhibition

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.