SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer
SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer
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DOI：
10.1007/s10142-023-01075-3
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发表时间：
2023-05
影响因子：
2.9
通讯作者：
Zhen Zheng;Xiao Li;Bikang Yang;Qinyang Xu;Xiaolu Zhu;Lipeng Hu;Y. Teng
中科院分区：
文献类型：
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作者：
Zhen Zheng;Xiao Li;Bikang Yang;Qinyang Xu;Xiaolu Zhu;Lipeng Hu;Y. Teng
卵巢癌是妇科恶性肿瘤中预后最差的一种。顺铂（Cisplatin，CDDP）是治疗卵巢癌最常用的药物之一，但由于内源性或获得性耐药，复发和转移是常见的。ATP结合盒（ABC）转运蛋白的高表达是OC化疗耐药的重要机制，但在OC治疗中靶向ABC转运蛋白仍是一个挑战。通过分析TCGA和GEO公开数据集，确定OC对CDDP反应中分拣蛋白相关受体1（SORL 1; SorLA）的表达。采用免疫组化和蛋白质印迹法检测SORL 1在顺铂敏感和耐药OC组织和细胞中的表达水平。通过CCK-8和细胞凋亡实验证实SORL 1对OC顺铂耐药的体外作用。皮下异种移植模型验证了SORL 1在OC中的体内意义。最后，通过免疫共沉淀、基因集富集分析和免疫荧光分析，揭示了SORL 1调控OC顺铂耐药的分子机制。这项研究表明，SORL 1与CDDP耐药性密切相关，并预测OC的预后不良。体内异种移植实验表明，SORL 1敲低显著增强了CDDP对CDDP耐药OC细胞的作用。SORL 1的沉默在机制上抑制了早期内体抗原1（EEA 1）通路，这阻碍了ATP结合盒B亚家族成员1（ABCB 1）的稳定性，使CDDP耐药OC细胞对CDDP敏感。这项研究的结果表明，靶向SORL 1可能是一种有前途的治疗方法，克服CDDP耐药的OC。
Ovarian cancer (OC) has the worst prognosis among gynecological malignancies. Cisplatin (CDDP) is one of the most commonly used treatments for OC, but recurrence and metastasis are common due to endogenous or acquired resistance. High expression of ATP-binding cassette (ABC) transporters is an important mechanism of resistance to OC chemotherapy, but targeting ABC transporters in OC therapy remains a challenge. The expression of sortilin-related receptor 1 (SORL1; SorLA) in the response of OC to CDDP was determined by analysis of TCGA and GEO public datasets. Immunohistochemistry and western blotting were utilized to evaluate the expression levels of SORL1 in OC tissues and cells that were sensitive or resistant to CDDP treatment. The in vitro effect of SORL1 on OC cisplatin resistance was proven by CCK-8 and cell apoptosis assays. The subcutaneous xenotransplantation model verified the in vivo significance of SORL1 in OC. Finally, the molecular mechanism by which SORL1 regulates OC cisplatin resistance was revealed by coimmunoprecipitation, gene set enrichment analysis and immunofluorescence analysis. This study demonstrated that SORL1 is closely related to CDDP resistance and predicts a poor prognosis in OC. In vivo xenograft experiments showed that SORL1 knockdown significantly enhanced the effect of CDDP on CDDP-resistant OC cells. Mechanistically, silencing of SORL1 inhibits the early endosomal antigen 1 (EEA1) pathway, which impedes the stability of ATP-binding cassette B subfamily member 1 (ABCB1), sensitizing CDDP-resistant OC cells to CDDP. The findings of this study suggest that targeting SORL1 may represent a promising therapeutic approach for overcoming CDDP resistance in OC.