MAT2A inhibitor blocks the progression of esophageal squamous cell carcinoma and affects downstream signaling networks
10.3872/j.issn.1007-385x.2025.01.008
- VernacularTitle:MAT2A抑制剂阻断食管鳞状细胞癌进展及其对下游信号网络的影响
- Author:
Yuanfan XIAO
1
;
Jie CHEN
1
Author Information
1. 北京大学肿瘤医院 分子肿瘤研究室,北京 100143
- Publication Type:Journal Article
- Keywords:
esophageal squamous cell carcinoma(ESCC);
methionine adenosyltransferase 2(MAT2A);
methionine metabolism;
PF9366
- From:
Chinese Journal of Cancer Biotherapy
2025;32(1):56-63
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the role of methionine adenosyltransferase 2(MAT2A)in esophageal squamous cell carcinoma(ESCC)and evaluate the inhibitory effects of MAT2A inhibitor PF9366 on ESCC cells and its underlying molecular mechanisms.Methods:Human ESCC cell lines(KYSE450,KYSE510,KYSE180,and KYSE410)and normal esophageal epithelial cells(NEECs)were used in this study.S-adenosylmethionine(SAM)production in these cells was verified by ELISA assay.KYSE450 and KYSE510 cells were treated with various concentrations of PF9366(0,5,10,and 25 μmol/L).The inhibitory effects of PF9366 on methionine(MET)activity and proliferation of ESCC cells were assessed using ELISA,MTS assay,and plate cloning formation assay.RNA-seq was performed to observe the effects of PF9366 on downstream oncogenic signaling pathways in KYSE450 cells.KYSE450 and KYSE510 cell xenograft models were constructed in mice to observe the effects of PF9366 on tumor growth in vivo.Results:MET activity in ESCC cells was significantly higher than that in NEECs(P<0.01).Following PF9366 treatment,SAM activity and cellular proliferation in KYSE450 and KYSE510 cells were significantly inhibited(all P<0.01),with a clear dose-dependent inhibitory effect(all P<0.05).RNA-seq analysis revealed that 20 signaling pathways associated with carcinogenesis and progression were downregulated in PF9366-treated ESCC cells.In vivo xenograft experiments demonstrated that PF9366 treatment significantly inhibited the growth of ESCC cell-derived tumors in mice(all P<0.0001).Conclusion:MAT2A inhibitor PF9366 inhibits SAM production in ESCC cells,suppresses cell proliferation,and activates key downstream oncogenic signaling networks,suggesting that MAT2A,a key enzyme in methionine metabolism,is a potential therapeutic target for ESCC.
