Abstract
BackgroundThe signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment.MethodsIn this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in a patient-derived xenograft nude mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination, and immunofluorescence were utilized to evaluate the regulatory signaling pathway.ResultsOur research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, the therapeutic effects of genipin in a patient-derived HCC xenograft nude mice model were also demonstrated.ConclusionsIn conclusion, genipin showed therapeutic potential for HCC treatment by interacting with the SH2-STAT-3 domain and suppressing the activity of STAT-3. In the future, further research is planned to explore the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.
Highlights
The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling
Further research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3
Genipin can inhibit the phosphorylation of STAT-3 (Tyr) and decrease the expression of STAT-3 target gene in hepatocellular carcinoma (HCC) cells As a transcription factor, STAT-3 can regulate cell proliferation and angiogenesis through modulation of its downstream target genes, such as Bcl-2, vascular endothelial growth factor (VEGF), and SOCS-3 [23]
Summary
The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Several natural products, such as alantolactone and osthole, can suppress the phosphorylation and activation of STAT-3 as well as inhibit tumor progression in breast cancer by directly binding with the SH2 domain of STAT-3 [8, 9]. None of these candidate agents have been assessed for their binding affinity to STAT-3. Their selectivity with STAT-3 and other STAT family proteins still needs further exploration
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