Induction of immunoglobulin transcription factor 2 and resistance to MEK inhibitor in melanoma cells
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Eun-Hye Hur1,*, Bon-Kwan Goo1,*, Juhyun Moon1, Yunsuk Choi2, Jung Jin Hwang3, Choung-Soo Kim4, Kyun Seop Bae5, Jene Choi6, Suk Young Cho7, Sang-Hwa Yang8,10, Jeongbeob Seo9, Gilnam Lee9 and Je-Hwan Lee1
1Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2Division of Hematology and Hematological Malignancies, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
3Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
4Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
5Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
6Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
7Wuxi App Tec (Shanghai) Co., Ltd. Shanghai, China
8Department of Biotechnology, College of Life Science and Biotechnology, National Creative Research Initiatives Center for Inflammatory Response Modulation, Yonsei University, Seoul, Korea
9Department of Medicinal Chemistry, CHABIOMED Co., LTD., Seongnam-Si, Korea
10MD Healthcare, Inc., Seoul, Korea
*These authors contributed equally to this work
Je-Hwan Lee, email: email@example.com
Keywords: MAPK, resistance, ITF-2, beta-catenin, melanoma
Received: December 09, 2016 Accepted: April 11, 2017 Published: May 15, 2017
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.
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