The Experts below are selected from a list of 705 Experts worldwide ranked by ideXlab platform
Tsai-hsien Hung - One of the best experts on this subject based on the ideXlab platform.
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Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells
Cancer biology & therapy, 2015Co-Authors: Kowit-yu Chong, Chih-jung Hsu, Tsai-hsien Hung, Tsung-teng Huang, Tzu-hao Wang, Chihuei Wang, Chuan-mu Chen, Kong-bung Choo, Ching-ping TsengAbstract:Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human Uterus Sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx...
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Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
Oncotarget, 2014Co-Authors: Tsai-hsien Hung, Tsung-teng Huang, Kong-bung Choo, Ching-ping Tseng, Sheng-chi Hsu, Ching-yi Cheng, T.-y. Chen, Ying-wei Lan, Hsin-chih Lai, Chuan-mu ChenAbstract:// Tsai-Hsien Hung 1 , Sheng-Chi Hsu 4,5 , Ching-Yi Cheng 6 , Kong-Bung Choo 7 , Ching-Ping Tseng 1,2,3 , Tse-Ching Chen 4,5 , Ying-Wei Lan 1 , Tsung-Teng Huang 8 , Hsin-Chih Lai 1,2 , Chuan-Mu Chen 9,10,11 and Kowit-Yu Chong 1,2,3 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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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells.
The international journal of biochemistry & cell biology, 2014Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Kong-bung Choo, Ching-ping Tseng, Chih-jie Shen, Hui-ling Wang, Kowit-yu ChongAbstract:Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human Uterus Sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
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Abstract 1908: MDR1 gene overexpression confers resistance to C-MET inhibitor in multidrug resistant cancer cell line
Experimental and Molecular Therapeutics, 2012Co-Authors: Tsai-hsien Hung, Kowit-yu ChongAbstract:c-MET signaling is implicated in a wide variety of human malignancies. Hepatocyte growth factor (HGF) binding to the proto-oncogenic c-MET receptor lead to activate multiple tyrosine kinase signaling pathway. Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Recently, several reports have indicated that inhibition of c-MET signaling induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study from our laboratory also showed that the higher mRNA expression level of HGF, and its downstream genes including HGF receptor (c-Met) and urokinase (uPA) were detected in drug resistant Dx5-C5 cell compared with parental human Uterus Sarcoma MES-SA cell line. Furthermore, report indicated that the constitutive expression of P-glycoprotein (P-gp) is involved in the HGF/MET related pathway of MDR-positive human hepatocellular carcinoma cell line. Moreover, MDR1 gene overexpressed leukemia cell line also shown more resistance to tyrosine kinase inhibitor imatinib mesylate. These finding suggested that chemoresistant cancer cells may also develop a similar mechanism to against c-MET inhibitor. Our results shown: when treated both cell cancer lines with c-MET inhibitor PHA665752, we found that compared to parental MES-SA cells, the Dx5-C5 cells with highly expressed P-gp was more resistant to PHA665752, the resistance was also reversed by co-treatment of MDR inhibitor verapamil and PHA665752. In addition, when transfection of c-MET shRNA into Dx5-C5 and MES-SA cell line for 48 hrs, we found that the viability was decreased in the c-MET shRNA transfected Dx5-C5 cell line in a dose dependent manner but not in the MES-SA cell line. In conclusion, our study demonstrated that existence of P-glycoprotein in MDR cell line would attenuate c-MET inhibitor induced cell death and may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1908. doi:1538-7445.AM2012-1908
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Abstract 4914: Methylation profiling of CpG islands in multiple drug resistant cell line
Cellular and Molecular Biology, 2010Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Chih-jie Shen, Kowit-yu ChongAbstract:Multiple drug resistance (MDR) is a major issue to attenuate the effectiveness of chemotherapy to many human malignancies. Despite extensively investigation, MDR inhibitors have been discovered serve side effect. Recently, scientists have reported that proteasome inhibitor, Bertezomib (PS-341), induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study revealed that bertezomib inhibits DNA methyltransferase and led to DNA hypomethylation in myeloid leukemia. Despite its success, some patients are resistant to ongoing proteasome inhibitor treatment. These reports suggested that chemoresistant cell line may develop a novel mechanism to against proteasome inhibitor. To verify the hypothesis, we used human CpG island microarray to indentify epigenetic change and genes expression profile in parental human Uterus Sarcoma cell line (MES-SA) and MES-SA variant drug resistant cell line (Dx5-C5) Our data has shown that the global genes were hypomethylated in both PS-341 treated MES-SA and Dx5-C5 cell line. Furthermore, the Wnt signalling pathway and cell cycle related gene have significant altered in DNA methylation pattern of Dx5-C5. In summary, our study demonstrated that the cell cycle related gene(s) and upstream gene(s) of Wnt pathway altered its DNA methylation pattern and mRNA expression level in MDR cell line. These data may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4914.
Chuan-mu Chen - One of the best experts on this subject based on the ideXlab platform.
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Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells
Cancer biology & therapy, 2015Co-Authors: Kowit-yu Chong, Chih-jung Hsu, Tsai-hsien Hung, Tsung-teng Huang, Tzu-hao Wang, Chihuei Wang, Chuan-mu Chen, Kong-bung Choo, Ching-ping TsengAbstract:Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human Uterus Sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx...
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Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
Oncotarget, 2014Co-Authors: Tsai-hsien Hung, Tsung-teng Huang, Kong-bung Choo, Ching-ping Tseng, Sheng-chi Hsu, Ching-yi Cheng, T.-y. Chen, Ying-wei Lan, Hsin-chih Lai, Chuan-mu ChenAbstract:// Tsai-Hsien Hung 1 , Sheng-Chi Hsu 4,5 , Ching-Yi Cheng 6 , Kong-Bung Choo 7 , Ching-Ping Tseng 1,2,3 , Tse-Ching Chen 4,5 , Ying-Wei Lan 1 , Tsung-Teng Huang 8 , Hsin-Chih Lai 1,2 , Chuan-Mu Chen 9,10,11 and Kowit-Yu Chong 1,2,3 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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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells.
The international journal of biochemistry & cell biology, 2014Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Kong-bung Choo, Ching-ping Tseng, Chih-jie Shen, Hui-ling Wang, Kowit-yu ChongAbstract:Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human Uterus Sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
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Abstract 4914: Methylation profiling of CpG islands in multiple drug resistant cell line
Cellular and Molecular Biology, 2010Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Chih-jie Shen, Kowit-yu ChongAbstract:Multiple drug resistance (MDR) is a major issue to attenuate the effectiveness of chemotherapy to many human malignancies. Despite extensively investigation, MDR inhibitors have been discovered serve side effect. Recently, scientists have reported that proteasome inhibitor, Bertezomib (PS-341), induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study revealed that bertezomib inhibits DNA methyltransferase and led to DNA hypomethylation in myeloid leukemia. Despite its success, some patients are resistant to ongoing proteasome inhibitor treatment. These reports suggested that chemoresistant cell line may develop a novel mechanism to against proteasome inhibitor. To verify the hypothesis, we used human CpG island microarray to indentify epigenetic change and genes expression profile in parental human Uterus Sarcoma cell line (MES-SA) and MES-SA variant drug resistant cell line (Dx5-C5) Our data has shown that the global genes were hypomethylated in both PS-341 treated MES-SA and Dx5-C5 cell line. Furthermore, the Wnt signalling pathway and cell cycle related gene have significant altered in DNA methylation pattern of Dx5-C5. In summary, our study demonstrated that the cell cycle related gene(s) and upstream gene(s) of Wnt pathway altered its DNA methylation pattern and mRNA expression level in MDR cell line. These data may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4914.
Ching-ping Tseng - One of the best experts on this subject based on the ideXlab platform.
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Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells
Cancer biology & therapy, 2015Co-Authors: Kowit-yu Chong, Chih-jung Hsu, Tsai-hsien Hung, Tsung-teng Huang, Tzu-hao Wang, Chihuei Wang, Chuan-mu Chen, Kong-bung Choo, Ching-ping TsengAbstract:Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human Uterus Sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx...
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Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
Oncotarget, 2014Co-Authors: Tsai-hsien Hung, Tsung-teng Huang, Kong-bung Choo, Ching-ping Tseng, Sheng-chi Hsu, Ching-yi Cheng, T.-y. Chen, Ying-wei Lan, Hsin-chih Lai, Chuan-mu ChenAbstract:// Tsai-Hsien Hung 1 , Sheng-Chi Hsu 4,5 , Ching-Yi Cheng 6 , Kong-Bung Choo 7 , Ching-Ping Tseng 1,2,3 , Tse-Ching Chen 4,5 , Ying-Wei Lan 1 , Tsung-Teng Huang 8 , Hsin-Chih Lai 1,2 , Chuan-Mu Chen 9,10,11 and Kowit-Yu Chong 1,2,3 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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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells.
The international journal of biochemistry & cell biology, 2014Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Kong-bung Choo, Ching-ping Tseng, Chih-jie Shen, Hui-ling Wang, Kowit-yu ChongAbstract:Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human Uterus Sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
Kowit-yu Chong - One of the best experts on this subject based on the ideXlab platform.
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Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells
Cancer biology & therapy, 2015Co-Authors: Kowit-yu Chong, Chih-jung Hsu, Tsai-hsien Hung, Tsung-teng Huang, Tzu-hao Wang, Chihuei Wang, Chuan-mu Chen, Kong-bung Choo, Ching-ping TsengAbstract:Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human Uterus Sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx...
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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells.
The international journal of biochemistry & cell biology, 2014Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Kong-bung Choo, Ching-ping Tseng, Chih-jie Shen, Hui-ling Wang, Kowit-yu ChongAbstract:Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human Uterus Sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
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Abstract 1908: MDR1 gene overexpression confers resistance to C-MET inhibitor in multidrug resistant cancer cell line
Experimental and Molecular Therapeutics, 2012Co-Authors: Tsai-hsien Hung, Kowit-yu ChongAbstract:c-MET signaling is implicated in a wide variety of human malignancies. Hepatocyte growth factor (HGF) binding to the proto-oncogenic c-MET receptor lead to activate multiple tyrosine kinase signaling pathway. Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Recently, several reports have indicated that inhibition of c-MET signaling induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study from our laboratory also showed that the higher mRNA expression level of HGF, and its downstream genes including HGF receptor (c-Met) and urokinase (uPA) were detected in drug resistant Dx5-C5 cell compared with parental human Uterus Sarcoma MES-SA cell line. Furthermore, report indicated that the constitutive expression of P-glycoprotein (P-gp) is involved in the HGF/MET related pathway of MDR-positive human hepatocellular carcinoma cell line. Moreover, MDR1 gene overexpressed leukemia cell line also shown more resistance to tyrosine kinase inhibitor imatinib mesylate. These finding suggested that chemoresistant cancer cells may also develop a similar mechanism to against c-MET inhibitor. Our results shown: when treated both cell cancer lines with c-MET inhibitor PHA665752, we found that compared to parental MES-SA cells, the Dx5-C5 cells with highly expressed P-gp was more resistant to PHA665752, the resistance was also reversed by co-treatment of MDR inhibitor verapamil and PHA665752. In addition, when transfection of c-MET shRNA into Dx5-C5 and MES-SA cell line for 48 hrs, we found that the viability was decreased in the c-MET shRNA transfected Dx5-C5 cell line in a dose dependent manner but not in the MES-SA cell line. In conclusion, our study demonstrated that existence of P-glycoprotein in MDR cell line would attenuate c-MET inhibitor induced cell death and may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1908. doi:1538-7445.AM2012-1908
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Abstract 4914: Methylation profiling of CpG islands in multiple drug resistant cell line
Cellular and Molecular Biology, 2010Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Chih-jie Shen, Kowit-yu ChongAbstract:Multiple drug resistance (MDR) is a major issue to attenuate the effectiveness of chemotherapy to many human malignancies. Despite extensively investigation, MDR inhibitors have been discovered serve side effect. Recently, scientists have reported that proteasome inhibitor, Bertezomib (PS-341), induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study revealed that bertezomib inhibits DNA methyltransferase and led to DNA hypomethylation in myeloid leukemia. Despite its success, some patients are resistant to ongoing proteasome inhibitor treatment. These reports suggested that chemoresistant cell line may develop a novel mechanism to against proteasome inhibitor. To verify the hypothesis, we used human CpG island microarray to indentify epigenetic change and genes expression profile in parental human Uterus Sarcoma cell line (MES-SA) and MES-SA variant drug resistant cell line (Dx5-C5) Our data has shown that the global genes were hypomethylated in both PS-341 treated MES-SA and Dx5-C5 cell line. Furthermore, the Wnt signalling pathway and cell cycle related gene have significant altered in DNA methylation pattern of Dx5-C5. In summary, our study demonstrated that the cell cycle related gene(s) and upstream gene(s) of Wnt pathway altered its DNA methylation pattern and mRNA expression level in MDR cell line. These data may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4914.
Kong-bung Choo - One of the best experts on this subject based on the ideXlab platform.
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Wnt pathway activation and ABCB1 expression account for attenuation of Proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells
Cancer biology & therapy, 2015Co-Authors: Kowit-yu Chong, Chih-jung Hsu, Tsai-hsien Hung, Tsung-teng Huang, Tzu-hao Wang, Chihuei Wang, Chuan-mu Chen, Kong-bung Choo, Ching-ping TsengAbstract:Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human Uterus Sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx...
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Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
Oncotarget, 2014Co-Authors: Tsai-hsien Hung, Tsung-teng Huang, Kong-bung Choo, Ching-ping Tseng, Sheng-chi Hsu, Ching-yi Cheng, T.-y. Chen, Ying-wei Lan, Hsin-chih Lai, Chuan-mu ChenAbstract:// Tsai-Hsien Hung 1 , Sheng-Chi Hsu 4,5 , Ching-Yi Cheng 6 , Kong-Bung Choo 7 , Ching-Ping Tseng 1,2,3 , Tse-Ching Chen 4,5 , Ying-Wei Lan 1 , Tsung-Teng Huang 8 , Hsin-Chih Lai 1,2 , Chuan-Mu Chen 9,10,11 and Kowit-Yu Chong 1,2,3 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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FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells.
The international journal of biochemistry & cell biology, 2014Co-Authors: Tsai-hsien Hung, Chuan-mu Chen, Kong-bung Choo, Ching-ping Tseng, Chih-jie Shen, Hui-ling Wang, Kowit-yu ChongAbstract:Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human Uterus Sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
