PMID- 36610164 OWN - NLM STAT- MEDLINE DCOM- 20230112 LR - 20230112 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 109 DP - 2023 Jan TI - Inhibition of STAT3 signaling contributes to the anti-melanoma effects of chrysoeriol. PG - 154572 LID - S0944-7113(22)00660-2 [pii] LID - 10.1016/j.phymed.2022.154572 [doi] AB - 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. CI - Copyright (c) 2022. Published by Elsevier GmbH. FAU - Liu, Yu-Xi AU - Liu YX AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Chen, Ying-Jie AU - Chen YJ AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: 19482256@life.hkbu.edu.hk. FAU - Xu, Bo-Wen AU - Xu BW AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Fu, Xiu-Qiong AU - Fu XQ AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Ding, Wen-Jun AU - Ding WJ AD - Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. FAU - Li, Sze-Man Amy AU - Li SA AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Wang, Xiao-Qi AU - Wang XQ AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Wu, Jia-Ying AU - Wu JY AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Wu, Ying AU - Wu Y AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. FAU - Dou, Xiaobing AU - Dou X AD - School of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China. FAU - Liu, Bin AU - Liu B AD - Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: xmhoolv@163.com. FAU - Yu, Zhi-Ling AU - Yu ZL AD - Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China; Research and Development Centre for Natural Health Products, HKBU Institute for Research and Continuing Education, Shenzhen, China. Electronic address: zlyu@hkbu.edu.hk. LA - eng PT - Journal Article DEP - 20221120 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - Q813145M20 (chrysoeriol) RN - 0 (STAT3 Transcription Factor) RN - 0 (Flavones) SB - IM MH - Animals MH - Mice MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction MH - *Melanoma/drug therapy MH - *Flavones/pharmacology MH - Cell Proliferation MH - Cell Line, Tumor MH - Apoptosis MH - Tumor Microenvironment OTO - NOTNLM OT - Chrysoeriol OT - Melanoma OT - STAT3 OT - Src OT - Tumor microenvironment COIS- Declaration of Competing Interest The authors declare no competing financial interest. EDAT- 2023/01/08 06:00 MHDA- 2023/01/13 06:00 CRDT- 2023/01/07 18:06 PHST- 2022/07/04 00:00 [received] PHST- 2022/11/09 00:00 [revised] PHST- 2022/11/19 00:00 [accepted] PHST- 2023/01/08 06:00 [pubmed] PHST- 2023/01/13 06:00 [medline] PHST- 2023/01/07 18:06 [entrez] AID - S0944-7113(22)00660-2 [pii] AID - 10.1016/j.phymed.2022.154572 [doi] PST - ppublish SO - Phytomedicine. 2023 Jan;109:154572. doi: 10.1016/j.phymed.2022.154572. Epub 2022 Nov 20.