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Int. J. Mol. Sci. 2018, 19(7), 1981; https://doi.org/10.3390/ijms19071981

Label-Free Quantitative Proteomics Combined with Biological Validation Reveals Activation of Wnt/β-Catenin Pathway Contributing to Trastuzumab Resistance in Gastric Cancer

1
Department of Medicinal Chemistry, Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong 637100, China
2
Innovative Platform of Basic Medical Sciences, Department of Microbiology and Immunology, School of Basic Medical Sciences, North Sichuan Medical College, Nanchong 637100, China
3
School of Pharmaceutical Sciences and Innovative Drug Research Center, Chongqing University, Chongqing 401331, China
4
Department of Preventive Medicine, North Sichuan Medical College, Nanchong 637100, China
These two authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 6 June 2018 / Revised: 30 June 2018 / Accepted: 4 July 2018 / Published: 6 July 2018
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Resistance to trastuzumab, which specifically target HER2-positive breast and gastric cancer, can develop ultimately in cancer patients. However, the underlying mechanisms of resistance in gastric cancer have not been fully elucidated. Here, we established trastuzumab-resistant MKN45 and NCI N87 gastric cancer sublines from their parental cells. The resistant cells exhibited characteristics of epithelial-mesenchymal transition (EMT) and acquired higher migratory and invasive capacities. To exploit the activated pathways and develop new strategies to overcome trastuzumab resistance, we investigated MKN45 and MKN45/R cells via label-free quantitative proteomics, and found pathways that were altered significantly in MKN45/R cells, with the Wnt/β-catenin pathway being the most significant. We further confirmed the activation of this pathway by detecting its key molecules in MKN45/R and NCI N87/R cells via Western blot, in which Wnt3A, FZD6, and CTNNB1 increased, whereas GSK-3β decreased, manifesting the activation of the Wnt/β-catenin pathway. Correspondingly, inhibition of Wnt/β-catenin pathway by ICG-001, a specific Wnt/β-catenin inhibitor, preferentially reduced proliferation and invasion of trastuzumab-resistant cells and reversed EMT. Concurringly, CTNNB1 knockdown in stable cell lines potently sensitized cells to trastuzumab and induced more apoptosis. Taken together, our study demonstrates that the Wnt/β-catenin pathway mediates trastuzumab resistance, and the combination of Wnt/β-catenin inhibitors with trastuzumab may be an effective treatment option. View Full-Text
Keywords: gastric cancer; trastuzumab resistance; Wnt/β-catenin pathway; EMT; label-free quantitative proteomics gastric cancer; trastuzumab resistance; Wnt/β-catenin pathway; EMT; label-free quantitative proteomics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Liu, W.; Yuan, J.; Liu, Z.; Zhang, J.; Chang, J. Label-Free Quantitative Proteomics Combined with Biological Validation Reveals Activation of Wnt/β-Catenin Pathway Contributing to Trastuzumab Resistance in Gastric Cancer. Int. J. Mol. Sci. 2018, 19, 1981.

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