中国癌症杂志2025，Vol.35Issue(11)：1010-1018,9.DOI:10.19401/j.cnki.1007-3639.2025.11.003
Tepoxalin通过ABCB1影响结直肠癌细胞生长及耐药的分子机制研究
Mechanisms underlying tepoxalin-mediated regulation of cell growth and chemoresistance via ABCB1 in colorectal cancer
摘要
Abstract
Background and purpose:Colorectal cancer(CRC),ranking as the third most common malignant tumor globally,continues to pose a significant public health challenge due to its high incidence and mortality rates.Chemotherapy remains a cornerstone treatment for advanced CRC.However,its efficacy is often severely limited by the emergence of multidrug resistance(MDR).The drug efflux mediated by ABCB1 is a key mechanism underlying chemotherapeutic failure.Although the non-steroidal anti-inflammatory drug tepoxalin exhibits potential antitumor activity,it remains unclear whether it influences CRC progression and chemoresistance by targeting ABCB1.This study aimed to elucidate the mechanism by which tepoxalin suppresses CRC cell growth and reverses chemoresistance through the regulation of ABCB1.Methods:This study employed a multifaceted research strategy:Bioinformatics analysis was conducted using the DepMap,The Cancer Genome Atlas(TCGA),Genotype-Tissue Expression(GTEx)and Human Protein Atlas(HPA)databases to analyze ABCB1 expression profiles and drug sensitivity.In vitro,the cell counting kit-8(CCK-8)assay was used to assess cell proliferation and chemosensitivity,and IC50 values were calculated.A subcutaneous xenograft model in nude mice was established to evaluate the antitumor efficacy in vivo.The drug affinity responsive target stability(DARTS)assay was performed to validate the direct binding between tepoxalin and ABCB1 protein.Transcriptome sequencing and gene set enrichment analysis(GSEA)were utilized to identify downstream signaling pathways.Western blot and immunohistochemistry were applied to detect the expression changes of key proteins.The PI3K-Akt pathway inhibitor copanlisib was used for reverse validation.Statistical analysis was performed using SPSS 20.0 software,and graphs were generated using GraphPad Prism 8.0.1.A value of P＜0.05 was considered statistically significant.Results:ABCB1 was significantly overexpressed in CRC tissues and cell lines(P＜0.05).Cells with high ABCB1 expression exhibited increased sensitivity to tepoxalin(R=-0.323,P＜0.001).Tepoxalin directly bound to the ABCB1 protein and promoted its proteasomal degradation.In vivo,tepoxalin significantly inhibited the growth of xenograft tumors(P＜0.01)and downregulated the expression of ABCB1 and Ki-67 proliferation index in tumor tissues.Transcriptomic analysis revealed that tepoxalin suppressed the PI3K-Akt signaling pathway[GSEA,false discovery rate(FDR)＜0.05],leading to reduced transcriptional expression of ABCB1.This effect was replicated using the PI3K-Akt pathway inhibitor copanlisib.Ultimately,tepoxalin synergistically enhanced the efficacy of 5-fluorouracil(5-FU)through the aforementioned actions.Conclusion:Tepoxalin targets ABCB1 through a dual-track mechanism:it directly binds to and destabilizes the ABCB1 protein while simultaneously downregulating its transcriptional expression via inhibition of the PI3K-Akt pathway.This coordinated action can synergistically inhibit CRC cell growth and effectively reverse chemoresistance,offering a novel potential therapeutic strategy for overcoming drug resistance in CRC.关键词
结直肠癌/ABCB1/Tepoxalin/细胞生长/化疗耐药Key words
Colorectal cancer/ABCB1/Tepoxalin/Cell growth/Chemoresistance分类
医药卫生引用本文复制引用
何治军,金丽雯,郭端城,徐继..Tepoxalin通过ABCB1影响结直肠癌细胞生长及耐药的分子机制研究[J].中国癌症杂志,2025,35(11):1010-1018,9.基金项目
浦东新区卫生健康委员会卫生计生科研项目(PW2022A-24). Health and Family Planning Scientific Research Project of Pudong New Area Health Committee(PW2022A-24). （PW2022A-24）
