Lactic acid activates the SOX9-TRAF2 signaling pathway in tumor-associated macrophages to promote chemotherapy resistance in colon cancer
10.12007/j.issn.0258-4646.2025.07.004
- VernacularTitle:乳酸激活肿瘤相关巨噬细胞中SOX9-TRAF2信号通路促进结肠癌化疗耐药
- Author:
Bin ZHAO
1
;
Jipan LIU
;
Li ZHANG
;
Yabin LIU
Author Information
1. 衡水市人民医院肛肠和小儿外科,河北 衡水 053000
- Publication Type:Journal Article
- Keywords:
lactic acid;
tumor-associated macrophage;
SOX9-TRAF2 signaling pathway;
colon cancer;
chemotherapy resistance
- From:
Journal of China Medical University
2025;54(7):595-602
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effect of lactic acid(Lac)on chemotherapy resistance in colon cancer through activation of the SOX9-TRAF2 signaling pathway in tumor-associated macrophages(TAMs).Methods A chemotherapy-resistant colon cancer cell line(SW480-R)was established using a gradient exposure method.M0 macrophages were treated with 0,5,10,or 20 mmol/L Lac.Levels of trans-forming growth factorβ(TGF-β)and arginase 1(Arg1)in the supernatant were measured by ELISA.M0 macrophages were then treated with 0 or 20 mmol/L Lac,either alone or in combination with SOX9knockdown.SW480-R cells were treated with conditioned medium(CM)derived from the macrophage treatments(0 mmol/L Lac-CM,20 mmol/L Lac-CM,or 20 mmol/L Lac+si-SOX9-CM).Cell viability was assessed using the MTT assay,and cell migration was evaluated using Transwell assays.SOX9 protein expression was measured via Western blotting.TRAF2 ubiquitination and protein expression were evaluated after SOX9knockdown in SW480-R cells.The effect of Lac on chemotherapy resistance in vivo was assessed using a 5-FU and Lac co-intervention model.Results Lac treatment significantly increased TGF-βand Arg1 levels in macrophage supernatants(both P<0.05).Compared to the 0 mmol/L Lac-CM group,the 20 mmol/L Lac-CM group showed significantly increased SW480-R cell viability,migration,and SOX9 protein expression(all P<0.05).SOX9knockdown partially reversed the Lac-in-duced changes in SW480-R cell behavior.Furthermore,SOX9knockdown increased TRAF2 ubiquitination and decreased TRAF2 protein expression(both P<0.05).In vivo,5-FU effectively inhibited tumor growth,whereas Lac administration attenuated the therapeutic efficacy of 5-FU.Conclusion Lac promotes chemotherapy resistance in colon cancer by activating the SOX9-TRAF2 signaling pathway in TAMs.
