The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids

doi:10.1038/onc.2016.195

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Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/17163

Title:	The ERK-ZEB1 pathway mediates epithelial-mesenchymal transition in pemetrexed resistant lung cancer cells with suppression by vinca alkaloids
Authors:	Chiu, L.-Y. Hsin, I.-L. Yang, T.-Y. Sung, W.-W. Chi, J.-Y. Chang, J.T. Ko, J.-L. Sheu, G.-T.
Contributors:	醫學研究所
Date:	2017-01
Issue Date:	2017-02-14T09:22:12Z (UTC)
Publisher:	Nature Publishing Group
ISSN:	09509232
Abstract:	High thymidylate synthase (TS) level in cancer tissue is considered to result in resistance to pemetrexed therapy for advanced stages of nonsquamous non-small cell lung cancers. To further investigate the mechanism of pemetrexed resistance and potential prognostic outcomes in lung cancer, we established pemetrexed-resistant lung adenocarcinoma cell sublines from CL1 harboring a mutated TP53 gene (R248W) and A549 harboring wild-type TP53. We found the TS expression is upregulated in both pemetrexed-resistant sublines and the reduced TS level achieved through shRNA inhibition resulted in higher pemetrexed sensitivity. We also demonstrated that the acquisitions of pemetrexed resistance enhances epithelial-mesenchymal transition (EMT) in vivo with a mice animal model and in vitro with CL1 and A549 sublines, which was associated with upregulation of ZEB1 which, in turn, downregulates E-cadherin and upregulates fibronectin. When ERK1/2 phosphorylation was reduced by an inhibitor (U0126) or siRNA inhibition, both pemetrexed-resistant sublines reduced their migration and invasion abilities. Therefore, the ERK-mediated pathways induce apoptosis with pemetrexed treatment, and may in turn mediate EMT when cancer cells are resistant to pemetrexed. We further demonstrated that the growth of pemetrexed-resistant tumors could be inhibited by vinblastine in vivo and vincristine in vitro. Our data indicate that pemetrexed resistance could be relieved by non-cross-resistant chemotherapeutic drugs such as vinca alkaloids and might be independent to TP53 status. Furthermore, the phosphorylation of ERK was reduced by vincristine. This finding provides a new insight for overcoming pemetrexed resistance and metastasis by application of vinca alkaloids.
URI:	http://dx.doi.org/10.1038/onc.2016.195 https://ir.csmu.edu.tw:8080/ir/handle/310902500/17163
Relation:	Oncogene,Volume 36, Issue 2, 12 January 2017, Pages 242-253
Appears in Collections:	[醫學研究所] 期刊論文

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