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AKT/GSK3 介导的 Slug 表达通过上调 ERCC1 促进结直肠癌对奥沙利铂的耐药性。

The AKT/GSK3-Mediated Slug Expression Contributes to Oxaliplatin Resistance in Colorectal Cancer via Upregulation of ERCC1.

机构信息

Department of Laboratory Medicine, The Affiliated Anhui Provincial Hospital of Anhui Medical UniversityHefeiP.R. China.

Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese MedicineHefeiP.R. China.

出版信息

Oncol Res. 2020 Sep 1;28(4):423-438. doi: 10.3727/096504020X15877284857868. Epub 2020 Apr 24.

DOI:10.3727/096504020X15877284857868
PMID:32331534
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7851510/
Abstract

Although oxaliplatin serves as one of the first-line drugs prescribed for treating colorectal cancer (CRC), the therapeutic effect is disappointing due to drug resistance. So far, the molecular mechanisms mediating oxaliplatin resistance remain unclear. In this study, we found the chemoresistance in oxaliplatin-resistant HCT116 cells (HCT116/OXA) was mediated by the upregulation of ERCC1 expression. In addition, the acquisition of resistance induced epithelialmesenchymal transition (EMT) as well as the Slug overexpression. On the contrary, Slug silencing reversed the EMT phenotype, decreased ERCC1 expression, and ameliorated drug resistance. Further mechanistical studies revealed the enhanced Slug expression resulted from the activation of AKT/glycogen synthase kinase 3 (GSK3) signaling. Moreover, in CRC patients, coexpression of Slug and ERCC1 was observed, and increased Slug expression was significantly correlated with clinicopathological factors and prognosis. Taken together, the simultaneous inhibition of the AKT/GSK3/Slug axis may be of significance for surmounting metastasis and chemoresistance, thereby improving the therapeutic outcome of oxaliplatin.

摘要

尽管奥沙利铂是治疗结直肠癌 (CRC) 的一线药物之一，但由于耐药性，其治疗效果并不理想。到目前为止，介导奥沙利铂耐药的分子机制尚不清楚。在这项研究中，我们发现奥沙利铂耐药的 HCT116 细胞 (HCT116/OXA) 的耐药性是通过 ERCC1 表达上调介导的。此外，耐药性的获得诱导了上皮-间充质转化 (EMT) 以及 Slug 的过表达。相反，Slug 的沉默逆转了 EMT 表型，降低了 ERCC1 的表达，并改善了耐药性。进一步的机制研究表明，Slug 表达的增强是由于 AKT/糖原合酶激酶 3 (GSK3) 信号的激活。此外，在 CRC 患者中观察到 Slug 和 ERCC1 的共表达，并且 Slug 表达的增加与临床病理因素和预后显著相关。总之，同时抑制 AKT/GSK3/Slug 轴可能对克服转移和化疗耐药性具有重要意义，从而改善奥沙利铂的治疗效果。

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