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PMID: 25401518 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway.

Oncotarget ·Vol. 5 ·No. 23 ·2014-12-15 ·Pages 12273-90

Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, Lan YW, Huang TT, Lai HC, Chen CM, Chong KY

Abstract

Multidrug resistance in cancer cells arises from altered drug permeability of the cell. We previously reported activation of the Wnt pathway in ABCB1-overexpressed human uterus sarcoma drug-resistant MES-SA/Dx5 cells through active β-catenin and associated transactivation activities, and upregulation of Wnt-targeting genes. In this study, Wnt5A was found to be significantly upregulated in MES-SA/Dx5 and MCF7/ADR2 cells, suggesting an important role for the Wnt5A signaling pathway in cancer drug resistance. Higher cAMP response elements and Tcf/Lef transcription activities were shown in the drug-resistant cancer cells. However, expression of Wnt target genes and CRE activities was downregulated in Wnt5A shRNA stably-transfected MES-SA/Dx5 cells. Cell viability of the drug-resistant cancer cells was also reduced by doxorubicin treatment and Wnt5A shRNA transfection, or by Wnt5A depletion. The in vitro data were supported by immunohistochemical analysis of 24 paired breast cancer biopsies obtained pre- and post-chemotherapeutic treatment. Wnt5A, VEGF and/or ABCB1 were significantly overexpressed after treatment, consistent with clinical chemoresistance. Taken together, the Wnt5A signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and β-catenin-related genes in antagonizing the toxic effects of doxorubicin in the MDR cell lines and in clinical breast cancer samples.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B/biosynthesis Animals Blotting, Western Breast Neoplasms/drug therapy,metabolism Cell Line, Tumor Cyclic AMP-Dependent Protein Kinases/metabolism Drug Resistance, Multiple/physiology Drug Resistance, Neoplasm/physiology Female Flow Cytometry Gene Expression Regulation, Neoplastic Humans Immunohistochemistry In Situ Nick-End Labeling Mice Mice, Nude Proto-Oncogene Proteins/metabolism Real-Time Polymerase Chain Reaction Signal Transduction/physiology Transfection Wnt Proteins/metabolism Wnt-5a Protein Xenograft Model Antitumor Assays beta Catenin/metabolism
Chemicals
ABCB1 protein, human ATP Binding Cassette Transporter, Subfamily B CTNNB1 protein, human Proto-Oncogene Proteins WNT5A protein, human Wnt Proteins Wnt-5a Protein beta Catenin Cyclic AMP-Dependent Protein Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Hung Tsai-Hsien
Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Hsu Sheng-Chi
Cancer Molecular Diagnostic Laboratory, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China. Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China.
Cheng Ching-Yi
Department of Cosmetic Science, Graduate Institute of Health Industry Technology, Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan, Republic of China.
Choo Kong-Bung
Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
Tseng Ching-Ping
Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Chen Tse-Ching
Cancer Molecular Diagnostic Laboratory, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China. Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China.
Lan Ying-Wei
Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Huang Tsung-Teng
Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Lai Hsin-Chih
Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
Chen Chuan-Mu
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China. Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
Chong Kowit-Yu
Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.2631
Published
2014-12-15
Pages
12273-90
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4322984
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.2631 PMC Full Text View journal details
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