Inhibition of STAT3 signaling contributes to the anti-melanoma effects of chrysoeriol

Yu Xi Liu, Ying Jie Chen*, Bo Wen Xu, Xiu Qiong Fu, Wen Jun Ding, Sze Man Amy Li, Xiao Qi Wang, Jia Ying Wu, Ying Wu, Xiaobing Dou, Bin Liu*, Zhi Ling Yu*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

2 Citations (Scopus)

Abstract

Background: Melanoma is an aggressive malignancy with a high mortality rate. Signal transducer and activator of transcription 3 (STAT3), an oncoprotein, is considered as an effective target for treating melanoma. Chrysoeriol is a flavonoid compound, and possesses anti-tumor activity in lung cancer, breast cancer and multiple myeloma; while whether it has anti-melanoma effects is still not known. Chrysoeriol has been shown to restrain STAT3 signaling in an inflammation mouse model.

Purpose: In this study, the anti-melanoma effects of chrysoeriol and the involvement of STAT3 signaling in these effects were investigated.

Study design and Methods: CCK8 assays, 5-ethynyl-2′-deoxyuridine (EdU) staining, Annexin V-FITC/PI staining, Western blot analyses of cleaved caspase-9 and wound healing assays were used to study the anti-melanoma effects of chrysoeriol in cell models. A B16F10 melanoma bearing mouse model was used to evaluate the in vivo anti-melanoma effects of chrysoeriol. Indicators of cell proliferation, cell apoptosis and angiogeneis in melanoma tissues were detected by immunohistochemistry (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Immune cells in melanoma tissues were analyzed by flow cytometry. STAT3-overactivated cell models were used to investigate the involvement of STAT3 signaling in the anti-melanoma effects of chrysoeriol. Molecular dynamics (MD) simulations and surface plasmon resonance (SPR) assays were conducted to determine whether chrysoeriol binds to Src, an upstream kinase of STAT3.

Results: The results of cell experiments showed that chrysoeriol dose-dependently inhibited viability, proliferation and migration of, and induced apoptosis in, A375 and B16F10 melanoma cells. Chrysoeriol inhibited the phosphorylation of STAT3, and downregulated the expression of STAT3-target genes involved in melanoma growth and metastasis. Mouse studies showed that chrysoeriol restrained melanoma growth and tumor-related angiogenesis, and altered compositions of immune cells in melanoma microenvironment. Chrysoeriol also inhibited STAT3 signaling in B16F10 allografts. Chrysoeriol's viability-inhibiting effects were attenuated by over-activating STAT3 in A375 cells. Furthermore, chrysoeriol bound to the protein kinase domain of Src, and suppressed Src phosphorylation in melanoma cells and tissues.

Conclusion: This study, for the first time, demonstrates that chrysoeriol has anti-melanoma effects, and these effects are partially due to inhibiting STAT3 signaling. Our findings indicate that chrysoeriol has the potential to be developed into an anti-melanoma agent.

Original languageEnglish
Article number154572
Number of pages11
JournalPhytomedicine
Volume109
Early online date20 Nov 2022
DOIs
Publication statusPublished - Jan 2023

Scopus Subject Areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

User-Defined Keywords

  • Chrysoeriol
  • Melanoma
  • Src
  • STAT3
  • Tumor microenvironment

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