Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells
Identifieur interne : 000727 ( Main/Exploration ); précédent : 000726; suivant : 000728Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells
Auteurs : Yi-Sheng Liu [Taïwan] ; Yu-Chun Chang [Taïwan] ; Wei-Wen Kuo [Taïwan] ; Ming-Cheng Chen [Taïwan] ; Hsi-Hsien Hsu [Taïwan] ; Chuan-Chou Tu [Taïwan] ; Yu-Lan Yeh [Taïwan] ; Vijaya Padma Viswanadha [Inde] ; Po-Hsiang Liao [Taïwan] ; Chih-Yang Huang [Taïwan]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects.
Url:
DOI: 10.3390/cancers11070918
PubMed: 31261976
PubMed Central: 6678694
Affiliations:
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104</wicri:regionArea><wicri:noRegion>Taipei 104</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af9-cancers-11-00918">MacKay Medicine, Nursing and Management College, Taipei 112, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>MacKay Medicine, Nursing and Management College, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author><author><name sortKey="Tu, Chuan Chou" sort="Tu, Chuan Chou" uniqKey="Tu C" first="Chuan-Chou" last="Tu">Chuan-Chou Tu</name><affiliation wicri:level="1"><nlm:aff id="af10-cancers-11-00918">Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung 411, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung 411</wicri:regionArea><wicri:noRegion>Taichung 411</wicri:noRegion></affiliation></author><author><name sortKey="Yeh, Yu Lan" sort="Yeh, Yu Lan" uniqKey="Yeh Y" first="Yu-Lan" last="Yeh">Yu-Lan Yeh</name><affiliation wicri:level="1"><nlm:aff id="af11-cancers-11-00918">Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Pathology, Changhua Christian Hospital, Changhua 500</wicri:regionArea><wicri:noRegion>Changhua 500</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af12-cancers-11-00918">Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356</wicri:regionArea><wicri:noRegion>Miaoli 356</wicri:noRegion></affiliation></author><author><name sortKey="Viswanadha, Vijaya Padma" 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404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af18-cancers-11-00918">Department of Biotechnology, Asia University, Taichung 413, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Asia University, Taichung 413</wicri:regionArea><wicri:noRegion>Taichung 413</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31261976</idno><idno type="pmc">6678694</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678694</idno><idno type="RBID">PMC:6678694</idno><idno type="doi">10.3390/cancers11070918</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000453</idno><idno type="wicri:explorRef" 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uniqKey="Liu Y" first="Yi-Sheng" last="Liu">Yi-Sheng Liu</name><affiliation wicri:level="1"><nlm:aff id="af1-cancers-11-00918">Program for Aging, China Medical University, Taichung 404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Program for Aging, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-00918">Division of Hematology and Oncology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Division of Hematology and Oncology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802</wicri:regionArea><wicri:noRegion>Kaohsiung 802</wicri:noRegion></affiliation></author><author><name sortKey="Chang, Yu Chun" sort="Chang, Yu Chun" uniqKey="Chang Y" first="Yu-Chun" last="Chang">Yu-Chun Chang</name><affiliation wicri:level="1"><nlm:aff id="af3-cancers-11-00918">Graduate Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Graduate Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912</wicri:regionArea><wicri:noRegion>Pingtung 912</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cancers-11-00918">School of Chinese Medicine, China Medical University, Taichung 404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>School of Chinese Medicine, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation></author><author><name sortKey="Kuo, Wei Wen" sort="Kuo, Wei Wen" uniqKey="Kuo W" first="Wei-Wen" last="Kuo">Wei-Wen Kuo</name><affiliation wicri:level="1"><nlm:aff id="af5-cancers-11-00918">Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biological Science and Technology, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Ming Cheng" sort="Chen, Ming Cheng" uniqKey="Chen M" first="Ming-Cheng" last="Chen">Ming-Cheng Chen</name><affiliation wicri:level="1"><nlm:aff id="af6-cancers-11-00918">Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung 407</wicri:regionArea><wicri:noRegion>Taichung 407</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af7-cancers-11-00918">Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Faculty of Medicine, National Yang-Ming University, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author><author><name sortKey="Hsu, Hsi Hsien" sort="Hsu, Hsi Hsien" uniqKey="Hsu H" first="Hsi-Hsien" last="Hsu">Hsi-Hsien Hsu</name><affiliation wicri:level="1"><nlm:aff id="af8-cancers-11-00918">Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei 104</wicri:regionArea><wicri:noRegion>Taipei 104</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af9-cancers-11-00918">MacKay Medicine, Nursing and Management College, Taipei 112, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>MacKay Medicine, Nursing and Management College, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author><author><name sortKey="Tu, Chuan Chou" sort="Tu, Chuan Chou" uniqKey="Tu C" first="Chuan-Chou" last="Tu">Chuan-Chou Tu</name><affiliation wicri:level="1"><nlm:aff id="af10-cancers-11-00918">Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung 411, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung 411</wicri:regionArea><wicri:noRegion>Taichung 411</wicri:noRegion></affiliation></author><author><name sortKey="Yeh, Yu Lan" sort="Yeh, Yu Lan" uniqKey="Yeh Y" first="Yu-Lan" last="Yeh">Yu-Lan Yeh</name><affiliation wicri:level="1"><nlm:aff id="af11-cancers-11-00918">Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Pathology, Changhua Christian Hospital, Changhua 500</wicri:regionArea><wicri:noRegion>Changhua 500</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af12-cancers-11-00918">Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356</wicri:regionArea><wicri:noRegion>Miaoli 356</wicri:noRegion></affiliation></author><author><name sortKey="Viswanadha, Vijaya Padma" sort="Viswanadha, Vijaya Padma" uniqKey="Viswanadha V" first="Vijaya Padma" last="Viswanadha">Vijaya Padma Viswanadha</name><affiliation wicri:level="1"><nlm:aff id="af13-cancers-11-00918">Department of Biotechnology, Bharathiar University, Coimbatore 641046, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biotechnology, Bharathiar University, Coimbatore 641046</wicri:regionArea><wicri:noRegion>Coimbatore 641046</wicri:noRegion></affiliation></author><author><name sortKey="Liao, Po Hsiang" sort="Liao, Po Hsiang" uniqKey="Liao P" first="Po-Hsiang" last="Liao">Po-Hsiang Liao</name><affiliation wicri:level="1"><nlm:aff id="af14-cancers-11-00918">Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Graduate Institute of Basic Medical Science, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af15-cancers-11-00918">Cardiovascular research center, Hualien Tzu Chi Hospital, Hualien 970, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Cardiovascular research center, Hualien Tzu Chi Hospital, Hualien 970</wicri:regionArea><wicri:noRegion>Hualien 970</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af16-cancers-11-00918">Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970</wicri:regionArea><wicri:noRegion>Hualien 970</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Chih Yang" sort="Huang, Chih Yang" uniqKey="Huang C" first="Chih-Yang" last="Huang">Chih-Yang Huang</name><affiliation wicri:level="1"><nlm:aff id="af15-cancers-11-00918">Cardiovascular research center, Hualien Tzu Chi Hospital, Hualien 970, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Cardiovascular research center, Hualien Tzu Chi Hospital, Hualien 970</wicri:regionArea><wicri:noRegion>Hualien 970</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af16-cancers-11-00918">Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970</wicri:regionArea><wicri:noRegion>Hualien 970</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af17-cancers-11-00918">Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404</wicri:regionArea><wicri:noRegion>Taichung 404</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af18-cancers-11-00918">Department of Biotechnology, Asia University, Taichung 413, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Biotechnology, Asia University, Taichung 413</wicri:regionArea><wicri:noRegion>Taichung 413</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancers</title><idno type="eISSN">2072-6694</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Hepatocellular carcinoma (HCC) is a common fatal type of malignant tumor that has highly metastatic and recurrent properties. Fisetin is a natural flavonoid found in various vegetables and fruits which exhibits anti-cancer and anti-inflammatory properties, as well as other effects. Thus, we hypothesized that fisetin can act as an adjuvant therapy in cancer or drug-resistant cancer cells, and further investigated the molecular mechanisms underlying the development of drug-resistance in HCC cells. We found that fisetin effectively inhibited the cell viability of not only parental cells but also histone deacetylase inhibitors-resistant (HDACis-R) cells and enhanced the chemosensitivity of HCC cells. Interestingly, fisetin did not induce cell apoptosis through the activation of the endoplasmic reticulum (ER) stress sensor of protein kinase R (PKR)-like endoplasmic reticulum kinase, but rather through the non-canonical pathway of the protein phosphatase 1 (PP1)-mediated suppression of eIF2α phosphorylation. Moreover, fisetin-induced cell apoptosis was reversed by treatment with PP1 activator or eIF2α siRNA in HCC cells. Based on these observations, we suggest that PP1-eIF2α pathways are significantly involved in the effect of fisetin on HCC apoptosis. Thus, fisetin may act as a novel anticancer drug and new chemotherapy adjuvant which can improve the efficacy of chemotherapeutic agents and diminish their side-effects. </p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Huang, W S W" uniqKey="Huang W">W.S.-W. Huang</name></author><author><name sortKey="Lin, H Y" uniqKey="Lin H">H.-Y. Lin</name></author><author><name sortKey="Yeh, C B" uniqKey="Yeh C">C.-B. Yeh</name></author><author><name sortKey="Chen, L Y" uniqKey="Chen L">L.-Y. Chen</name></author><author><name sortKey="Chou, Y E" uniqKey="Chou Y">Y.-E. Chou</name></author><author><name sortKey="Yang, S F" uniqKey="Yang S">S.-F. 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Wang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Inde</li><li>Taïwan</li></country></list><tree><country name="Taïwan"><noRegion><name sortKey="Liu, Yi Sheng" sort="Liu, Yi Sheng" uniqKey="Liu Y" first="Yi-Sheng" last="Liu">Yi-Sheng Liu</name></noRegion><name sortKey="Chang, Yu Chun" sort="Chang, Yu Chun" uniqKey="Chang Y" first="Yu-Chun" last="Chang">Yu-Chun Chang</name><name sortKey="Chang, Yu Chun" sort="Chang, Yu Chun" uniqKey="Chang Y" first="Yu-Chun" last="Chang">Yu-Chun Chang</name><name sortKey="Chen, Ming Cheng" sort="Chen, Ming Cheng" uniqKey="Chen M" first="Ming-Cheng" last="Chen">Ming-Cheng Chen</name><name sortKey="Chen, Ming Cheng" sort="Chen, Ming Cheng" uniqKey="Chen M" first="Ming-Cheng" last="Chen">Ming-Cheng Chen</name><name sortKey="Hsu, Hsi Hsien" sort="Hsu, Hsi Hsien" uniqKey="Hsu H" first="Hsi-Hsien" last="Hsu">Hsi-Hsien Hsu</name><name sortKey="Hsu, Hsi Hsien" sort="Hsu, Hsi Hsien" uniqKey="Hsu H" first="Hsi-Hsien" last="Hsu">Hsi-Hsien Hsu</name><name sortKey="Huang, Chih Yang" sort="Huang, Chih Yang" uniqKey="Huang C" first="Chih-Yang" last="Huang">Chih-Yang Huang</name><name sortKey="Huang, Chih Yang" sort="Huang, Chih Yang" uniqKey="Huang C" first="Chih-Yang" last="Huang">Chih-Yang Huang</name><name sortKey="Huang, Chih Yang" sort="Huang, Chih Yang" uniqKey="Huang C" first="Chih-Yang" last="Huang">Chih-Yang Huang</name><name sortKey="Huang, Chih Yang" sort="Huang, Chih Yang" uniqKey="Huang C" first="Chih-Yang" last="Huang">Chih-Yang Huang</name><name sortKey="Kuo, Wei Wen" sort="Kuo, Wei Wen" uniqKey="Kuo W" first="Wei-Wen" last="Kuo">Wei-Wen Kuo</name><name sortKey="Liao, Po Hsiang" sort="Liao, Po Hsiang" uniqKey="Liao P" first="Po-Hsiang" last="Liao">Po-Hsiang Liao</name><name sortKey="Liao, Po Hsiang" sort="Liao, Po Hsiang" uniqKey="Liao P" first="Po-Hsiang" last="Liao">Po-Hsiang Liao</name><name sortKey="Liao, Po Hsiang" sort="Liao, Po Hsiang" uniqKey="Liao P" first="Po-Hsiang" last="Liao">Po-Hsiang Liao</name><name sortKey="Liu, Yi Sheng" sort="Liu, Yi Sheng" uniqKey="Liu Y" first="Yi-Sheng" last="Liu">Yi-Sheng Liu</name><name sortKey="Tu, Chuan Chou" sort="Tu, Chuan Chou" uniqKey="Tu C" first="Chuan-Chou" last="Tu">Chuan-Chou Tu</name><name sortKey="Yeh, Yu Lan" sort="Yeh, Yu Lan" uniqKey="Yeh Y" first="Yu-Lan" last="Yeh">Yu-Lan Yeh</name><name sortKey="Yeh, Yu Lan" sort="Yeh, Yu Lan" uniqKey="Yeh Y" first="Yu-Lan" last="Yeh">Yu-Lan Yeh</name></country><country name="Inde"><noRegion><name sortKey="Viswanadha, Vijaya Padma" sort="Viswanadha, Vijaya Padma" uniqKey="Viswanadha V" first="Vijaya Padma" last="Viswanadha">Vijaya Padma Viswanadha</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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