Open AccessThe AKT/GSK3-Mediated Slug Expression Contributes to Oxaliplatin Resistance in Colorectal Cancer via Upregulation of ERCC1
Author(s) -
Wei Wei,
Xiaodong Ma,
Guanmin Jiang,
Bin Shi,
Wen Zhong,
Cheng-Yi Sun,
Liang Zhao,
Hou Yan-jiao,
Hao Wang
Publication year - 2020
Publication title -
oncology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 57
eISSN - 1555-3906
pISSN - 0965-0407
DOI - 10.3727/096504020x15877284857868
Subject(s) - slug , oxaliplatin , downregulation and upregulation , ercc1 , protein kinase b , cancer research , colorectal cancer , gene silencing , gsk 3 , medicine , drug resistance , cancer , signal transduction , biology , microbiology and biotechnology , biochemistry , dna repair , gene , genetics , nucleotide excision repair
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.