Icaritin Targets P53 to Regulate DNA Damage Repair and FOXO Signaling Pathways to Inhibit Glioma Cell Growth
10.13865/j.cnki.cjbmb.2025.03.1347
- VernacularTitle:淫羊藿素靶向P53调控DNA损伤修复和FOXO信号通路抑制胶质瘤细胞生长
- Author:
Zhi-Qiong LUO
1
;
Zhuo-Yi WANG
;
Yong-Ping WANG
;
Xiao-Zhong CHEN
;
Jia YU
;
Sha CHENG
;
Ning-Ning ZAN
;
Bao-Fei SUN
;
Heng LUO
Author Information
1. 贵州省高等学校功能与疾病人脑组织库重点实验室,贵州医科大学,贵阳 550025;贵州医科大学药用植物功效与应用国家重点实验室,贵阳 550014
- Publication Type:Journal Article
- Keywords:
glioblastoma(GBM);
icaritin(ICT);
P53;
DNA damage response;
forkhead box protein O1(FOXO1)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(5):753-763
- CountryChina
- Language:Chinese
-
Abstract:
Icaritin(ICT)is an 8-isopentenylflavonoid,which is the main effective component of the tra-ditional Chinese medicine Epimedium.Previously,we found that Icaritin inhibits the growth of glioblasto-ma(GBM)cells.Herein we aim to study the in vivo anti-GBM effectiveness of Icaritin and explore its mechanism.The results of MTT assay,flow cytometry,comet assay and cellular immunofluorescence as-say in vitro showed that ICT inhibited the proliferation of four kinds of GBM cells,U87,U251,U118 and A172,induced early apoptosis(P＜0.001)and late apoptosis(P＜0.05)in U87 cells,induced DNA damage in U87 cells,and blocked the growth of U87 cells at the G0/G1 phase(P＜0.0001)in a concen-tration-time-dependent manner.In vivo subcutaneous tumor transplantation tumor experiments showed that feeding 200 mg/kg(P＜0.01)and 400 mg/kg(P＜0.001)ICT had a significant inhibitory effect on the growth of GBM subcutaneous tumors,and had no significant toxic effects on heart,liver,spleen,lung and kidney tissues.The results of network pharmacological analysis,molecular docking and cellular thermodynamic experiments showed that there were 26 possible target proteins between ICT and GBM,a-mong which the expression of p53 in GBM tissues was significantly(P＜0.001)higher than in normal tis-sues,and the binding energy of ICT and p53 was lower;cellular thermodynamic experiments verified that ICT significantly enriched the level of p53 in the living cells of GBM,which indicated that ICT could tar-get p53.The expression of key proteins in the DNA damage repair and apoptosis-associated FOXO signa-ling pathway was detected by ICT.The results showed that the expression of ATR(P＜0.01),P53(P＜0.001),P21(P＜0.05)and γ-H2AX(P＜0.05)was up-regulated,whereas the expression of Cyc-lin E1(P＜0.01),E2F1(P＜0.05),CDK2(P＜0.01),Rb(P＜0.001),p-Rb(P＜0.0001)and WRN(P＜0.0001)expression were down-regulated.There was no significant change in the expres-sion of FOXO 1 in the FOXO pathway or a significant down-regulation of its phosphorylation level.This study demonstrated that ICT could effectively inhibit the growth of GBM cells in vivo.It targets p53 to regulate the DNA damage repair pathway and FOXO signaling pathway to induce GBM cell cycle arrest and apoptosis.
