Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells
| Autor: | Juhyun Moon, Gilnam Lee, Suk Young Cho, Yunsuk Choi, Jene Choi, Choung-Soo Kim, Sang-Hwa Yang, Kyun-Seop Bae, Jeongbeob Seo, Je-Hwan Lee, Bon-Kwan Goo, Jung Jin Hwang, Eun-Hye Hur |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell Survival HL-60 Cells resistance 03 medical and health sciences 0302 clinical medicine Transcription Factor 4 Cell Line Tumor melanoma Medicine Gene silencing Humans Transcription factor Protein Kinase Inhibitors Wnt Signaling Pathway Mitogen-Activated Protein Kinase Kinases Oncogene business.industry MEK inhibitor Gene Expression Profiling Wnt signaling pathway beta-catenin TCF4 MAPK ITF-2 3. Good health Gene expression profiling Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Benzimidazoles RNA Interference business K562 Cells Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Primary or acquired resistance to MEK inhibitors has been a barrier to successful treatment with MEK inhibitors in many tumors. In this study, we analyzed genome-wide gene expression profiling data from 6 sensitive and 6 resistant cell lines to identify candidate genes whose expression changes are associated with responses to a MEK inhibitor, selumetinib (AZD6244). Of 62 identified differentially expressed genes, we selected Immunoglobulin Transcription Factor 2, also known as transcription factor 4 as a potential drug resistance marker for further analysis. This was because the ITF-2 expression increase in resistant cell lines was relatively high and a previous study has suggested that ITF-2 functions as an oncogene in human colon cancers. We also established an AZD6244 resistant cell line (M14/AZD-3) from an AZD6244 sensitive M14 cell line. The expression of the ITF-2 was elevated both in primary AZD6244 resistant cell line, LOX-IMVI and acquired resistant cell line, M14/AZD-3. Targeted silencing of ITF-2 by siRNA significantly enhanced susceptibility to AZD6244 in resistant cells. Wnt/β-catenin pathway was activated through direct interaction of p-ERK and GSK3β. Our results suggest that up-regulation of the ITF-2 gene expression is associated with cellular resistance to MEK inhibitors, and activation of Wnt signaling pathway through interaction of p-ERK and GSK3β seems to be a mechanism for increase of ITF-2. |
| Databáze: | OpenAIRE |
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