靶向Galectin-1克服食管鳞状细胞癌中紫杉醇耐药性

Targeting Galectin-1 Overcomes Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma

CANCER RESEARCH

影响因子:16.6

分区:医学1区 Top / 肿瘤学1区

发表日期:2024 Nov 15

作者: Liting Zhou, Jie Tian, Keke Wang, Yijie Ma, Xiaojie Chen, Hui Luo, Bingbing Lu, Nan Wang, Penglei Wang, Xuejiao Liu, Ran Zhao, Simin Zhao, Jiutao Wang, Wenna Nie, Hong Ge, Wenting Liu, Tingxuan Gu, Kangdong Liu, Mee-Hyun Lee, Xiang Li, Zigang Dong

DOI: 10.1158/0008-5472.CAN-23-2241

摘要

紫杉醇耐药性是食管鳞状细胞癌（ESCC）治疗中的一大障碍。深入理解紫杉醇耐药的机制，有助于发现预后生物标志物并改善治疗策略。本研究建立了获得性紫杉醇耐药的患者源异种移植模型，利用RNA测序鉴定了由LGALS1编码的半乳糖凝集素-1（Galectin-1）为关键的耐药介导因。临床数据与生理研究的整合分析显示，耐药患者血清中Galectin-1水平升高，并与紫杉醇治疗前后的治疗结局相关。将血清中耐药患者的血清暴露于细胞中，导致紫杉醇耐药性增强，且这一效应与血清中Galectin-1浓度密切相关。特异性清除耐药患者血清中的Galectin-1显著恢复紫杉醇敏感性，通过敲低或药理抑制剂OTX008抑制Galectin-1，增加对紫杉醇的敏感性。Galectin-1抑制作用降低β-连环蛋白的活性，从而抑制由Wnt/β-连环蛋白途径诱导的干细胞特性。此外，Galectin-1通过增加β-连环蛋白的核积累调控MDR1转录，促进耐药性增强。将OTX008与临床用紫杉醇制剂联合应用，在体内外均有效逆转了紫杉醇耐药性。血清中Galectin-1水平升高可作为ESCC对紫杉醇治疗反应的指标，为克服药物耐药提供潜在的治疗干预策略。意义：Galectin-1是食管鳞状细胞癌中紫杉醇耐药的关键介导因，可作为靶点以改善紫杉醇的疗效，具有广泛的癌症治疗潜力。

Abstract

Resistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft model of acquired paclitaxel resistance and used RNA sequencing to identify galectin-1, encoded by LGALS1, as a key mediator of resistance. Integrative analysis of clinical data and physiological studies indicated that serum galectin-1 levels were elevated in resistant patients and correlated with treatment outcomes before and during taxane therapy. Importantly, exposing cells to serum from resistant patients resulted in increased paclitaxel resistance compared to serum from sensitive patients, which was closely associated with galectin-1 concentrations in the serum. The specific clearance of galectin-1 from resistant patient serum significantly restored paclitaxel sensitivity, and inhibiting galectin-1, through knockdown or the pharmacologic inhibitor OTX008, increased sensitivity to paclitaxel. Galectin-1 inhibition reduced the activity of β-catenin, thereby inhibiting stem cell properties induced by the Wnt/β-catenin pathway. Furthermore, galectin-1 regulated MDR1 transcription through increased nuclear accumulation of β-catenin, thus increasing resistance to paclitaxel. Combining OTX008 with clinical taxane formulations effectively reversed paclitaxel resistance in vitro and in vivo. Elevated galectin-1 levels thus serve as an indicator of response to paclitaxel therapy in ESCC, offering a therapeutic intervention strategy to overcome drug resistance. Significance: Galectin-1 is a key mediator of paclitaxel resistance in esophageal squamous cell carcinoma that can be targeted to improve taxane efficacy, suggesting broad therapeutic potential for treating various cancer types.