CTO inhibits the in situ growth of glioblastoma in mice and regulates the metabolism and inflammatory phenotype of glioma-associated microglia
10.16352/j.issn.1001-6325.2025.04.0478
- VernacularTitle:CTO抑制小鼠胶质瘤细胞原位生长并调节相关小胶质细胞代谢及炎性表型
- Author:
Yunfan LI
1
;
Jiaming ZOU
;
Yucheng WANG
;
Rui JU
;
Lei GUO
Author Information
1. 中国医学科学院基础医学研究所 北京协和医学院基础学院 药理系,北京 100005
- Keywords:
tumor microenvironment;
carboxyamidotriazole orotate;
glioma-associated microglia
- From:
Basic & Clinical Medicine
2025;45(4):478-485
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effects and regulatory mechanisms of carboxyamidotriazole orotate(CTO)on the metabolism and inflammatory mediators of glioma-associated microglia(GAM).Methods Tumor volume was regularly monitored by in vivo imaging,and histological examination was performed to detect the extent of tumor in-filtration;non-targeted metabolomics analysis was used to detect the level of tricarboxylic acid cycle metabolites in cells;seahorse cell energy measurement method was used to detect the oxygen consumption rate(OCR)and extra-cellular acidification rate(ECAR)of cells;immunofluorescence was used to detect the degree of hypoxia in cells;quantitative PCR was used to detect the mRNA level of pro-cancer mediators M1/M2 in cells;Western blot was used to detect the protein level of hypoxia-inducible factor-1α(HIF-1α)and programmed death receptor-ligand 1(PD-L1).Results CTO inhibited the tumor progression in mice,and down-regulated the oxidative phosphorylation level and improved cell hypoxia in vitro(P＜0.01).It also downregulated the expression of pro-oncogenic mediators iNos,Arg-1,Il-10,and Irf4 in GAM(P＜0.01).When combined with lactate dehydrogenase inhibitor stiripentol(STP),CTO-induced enhancement of glycolysis and upregulation of PD-L1 expression in GAM was attenuated(P＜0.01),and the expressions of Arg-1 and Il-10 was further downregulated(P＜0.000 1).Conclusions CTO down-regulates the expression of several oncogenic genes in GAM and inhibits tumor progression in mice.Combined use of lactate dehydrogenase inhibitors can weaken the adverse effect of CTO and reduce the transcriptional level of GAM oncogenic mediators.
