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ARTICLE

The AKT/GSK3β-Mediated Slug Expression Contributes to Oxaliplatin Resistance in Colorectal Cancer via Upregulation of ERCC1

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* Department of Laboratory Medicine, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China †Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei, P.R. China
‡ Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, P.R. China
§ Department of General Surgery, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China
¶ Department of Pathology, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, P.R. China

Oncology Research 2020, 28(4), 423-438. https://doi.org/10.3727/096504020X15877284857868

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 epithelial–mesenchymal 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.

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