Journal
CANCER LETTERS
Volume 400, Issue -, Pages 194-202Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.02.029
Keywords
Non-small cell lung cancer; DDX17; Chemoresistance; Nucleocytoplasmic shuttle; beta-catenin
Categories
Funding
- National Natural Science Foundation of China [81401979, 81402944, 81572604]
- Science and Technology Department of Sichuan Province Foundation [2014SZ0020]
- China Postdoctoral Science Foundation [2014M552367]
Ask authors/readers for more resources
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity. Mechanistically, we demonstrate that DDX17 disassociates the E-cadherin/beta-catenin complex, resulting in beta-catenin nuclear translocation and subsequently augmenting the transcription of beta-catenin target genes. Moreover, we identify two nuclear localization signal (NLS) and four nuclear export signal (NES) sequences mediated DDX17 nucleocytoplasmic shuttling via an exportin/importin-dependent pathways. Interruption of dynamic nucleocytoplasmic shuttling of DDX17 impairs DDX17-mediating the activation of beta-catenin and acquired resistance in NSCLC cells. In conclusion, our findings reveal a novel and important mechanism by which DDX17 contributes to acquired gefitinib resistance through exportin/importin-dependent cytoplasmic shuttling and followed by activation of beta-catenin, and DDX17 inhibition may be a promising strategy to overcome acquired resistance of gefitinib in NSCLC patients. (C) 2017 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available