甘草酸通过抑制OGT-MDH1信号通路减轻三阴性乳腺癌对紫杉醇的耐药性  

Glycyrrhizic acid reduces paclitaxel resistance in triple-negative breast cancer by inhibiting the OGT-MDH1 signaling pathway

作　　者：于凭洋 李金阳 窦赫 肖敏[1] YU Pingyang;LI Jinyang;DOU He;XIAO Min(Department of Breast Surgery,Harbin Medical University Cancer Hospital,Harbin 150081;Department of Pathogenic Biology,School of Basic Medical Sciences,Harbin Medical University,Harbin 150081,Heilongjiang,China)

机构地区：[1]哈尔滨医科大学附属肿瘤医院乳腺外科,黑龙江哈尔滨150081 [2]哈尔滨医科大学基础医学院病原生物学教研室,黑龙江哈尔滨150081

出　　处：《癌变.畸变.突变》2025年第1期33-38,共6页Carcinogenesis,Teratogenesis & Mutagenesis

基　　金：国家自然科学基金(82372940)。

摘　　要：目的:紫杉醇耐药是三阴性乳腺癌化疗失败的重要原因之一,本研究探讨甘草酸(GA)对三阴性乳腺癌紫杉醇(PTX)耐药细胞的增敏效果,并研究其机制。方法:以对紫杉醇耐药的MDA-MB-231细胞和BT-20细胞为研究对象,将细胞分为PTX处理组,及低、中、高剂量GA联用组(在PTX处理的基础上,分别加入2.5、5、10μmol/L的GA),采用磺酰罗丹明B比色法检测细胞活力。将细胞分为DMSO对照组、40 nmol/L PTX处理组、10μmol/L GA处理组、40 nmol/L PTX和10μmol/L GA联用组,采用细胞集落形成实验检测细胞增殖活力,流式细胞术检测细胞凋亡,Western blot实验检测Bcl-2、Bax、c-PARP、OGT和MDH1蛋白水平。结果:使用2.5、5和10μmol/L GA联用PTX处理PTX耐药细胞5 d,磺酰罗丹明B比色法检测结果显示与PTX组相比,GA联用PTX导致三阴性乳腺癌PTX耐药细胞活力下降并呈剂量依赖性。细胞集落形成实验结果显示,与对照组比较,GA联用PTX组细胞的集落形成率降低。流式细胞术结果显示,与PTX组比较,GA联用PTX处理耐药MDA-MB-231细胞48和72 h后,subG1群细胞的比例增加。Western blot实验显示GA联用PTX组细胞Bcl-2蛋白表达水平降低,Bax和c-PARP的蛋白表达水平升高。Western blot实验结果显示GA联用PTX显著抑制O-GlcNAcylation糖基化修饰、OGT和MDH1蛋白的表达水平。结论:甘草酸可以通过抑制OGT-MDH1信号通路显著增强PTX耐药细胞对紫杉醇的敏感性,减轻三阴性乳腺癌对紫杉醇的耐药性。OBJECTIVE:Paclitaxel resistance(PR)is a significant reason for chemotherapy failure in triple-negative breast cancer(TNBC).This study investigated the sensitizing effect of glycyrrhetinic acid(GA)on paclitaxel(PTX)resistant cells in TNBC and its mechanism of action.METHODS:PTX-resistant TNBC cell lines,MDA-MB-231 and BT-20,were used.Cells were divided into PTX treatment groups and low,medium,and high-dose GA combined groups(PTX treatment plus 2.5,5 or 10μmol/L GA).Cell viability was assessed using the Sulforhodamine B colorimetric assay.In addition,cells were divided into DMSO control group,40 nmol/L PTX treatment group,10μmol/L GA treatment group,and 40 nmol/L PTX and 10μmol/L GA combined group.Colony formation assay was performed to detect cell proliferation,and flow cytometry was used to detect cell apoptosis.Western blot experiments were conducted to measure the protein levels of Bcl-2,Bax,c-PARP,OGT,and MDH1.RESULTS:MDA-MB-231 were treated with 2.5,5 and 10μmol/L GA combined with PTX for 5 days.The results of sulforhodamine B colorimetric assay showed that compared with the PTX group,the combined treatment led to a decrease in the viability of the cells in a dose-dependent manner.The results of cell colony formation assay showed that compared with the control group,the colony formation rate of cells in the combined treatment group was reduced.Flow cytometry results showed that compared with the PTX group,the proportion of subG1 group cells increased after the combined treatment for 48 and 72 h.Western blot experiments showed that the expression level of Bcl-2 protein in the combined treatment group was reduced,and the expression levels of Bax and c-PARP proteins were increased.Western blot results showed that the combined treatment significantly inhibited O-GlcNAcylation glycosylation modification,and OGT and MDH1 protein expression levels.CONCLUSION:Glycyrrhetinic acid significantly enhanced the sensitivity of TNBC PTX-resistant cells to paclitaxel by inhibiting the OGT-MDH1 signaling pathway.

关 键 词：甘草酸 OGT-MDH1信号通路 三阴性乳腺癌 紫杉醇 耐药 

分 类 号：R738.1[医药卫生—肿瘤] R730.5[医药卫生—临床医学]