Research Papers:
Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
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Abstract
Tsai-Hsien Hung1, Sheng-Chi Hsu4,5, Ching-Yi Cheng6, Kong-Bung Choo7, Ching-Ping Tseng1,2,3, Tse-Ching Chen4,5, Ying-Wei Lan1, Tsung-Teng Huang8, Hsin-Chih Lai1,2, Chuan-Mu Chen9,10,11 and Kowit-Yu Chong1,2,3
1 Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
2 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
3 Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
4 Cancer Molecular Diagnostic Laboratory, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China
5 Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan, Republic of China
6 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
7 Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia
8 Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China
9 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China
10 Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
11 Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
Correspondence:
Kowit Yu Chong, email:
Keywords: Multiple Drug Resistance, Wnt5A, shRNA, Cell cycle, apoptosis
Received: June 17, 2014 Accepted: October 23, 2014 Published: October 24, 2014
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.
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