YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling
10.1016/j.jpha.2023.11.008
- Author:
Sui HUA
1
;
Deng WANLI
;
Chai QIONG
;
Han BING
;
Zhang YULI
;
Wei ZHENZHEN
;
Li ZAN
;
Wang TING
;
Feng JILING
;
Yuan MAN
;
Tang QINGFENG
;
Xu HONGXI
Author Information
1. Medical Experiment Center,Jiading Branch of Shanghai Ceneral Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,201803,China;Translational Medicine Research Center for Cancer Prevention and Treatment,Shanghai General Hospital Jiading Branch-School of Pharmacy of Shanghai University of Traditional Chinese Medicine Joint Laboratory,Shanghai,201803,China
- Keywords:
Tumor microenvironment;
Intestinal epithelial cells;
Treg/Th17 cells;
Metabolism;
Wnt5a/JNK signaling;
Tumorigenesis
- From:
Journal of Pharmaceutical Analysis
2024;14(4):525-541
- CountryChina
- Language:Chinese
-
Abstract:
The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.
