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Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells

1
Program for Aging, China Medical University, Taichung 404, Taiwan
2
Division of Hematology and Oncology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
3
Graduate Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
4
School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
5
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan
6
Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan
7
Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan
8
Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan
9
MacKay Medicine, Nursing and Management College, Taipei 112, Taiwan
10
Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung 411, Taiwan
11
Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan
12
Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan
13
Department of Biotechnology, Bharathiar University, Coimbatore 641046, India
14
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan
15
Cardiovascular research center, Hualien Tzu Chi Hospital, Hualien 970, Taiwan
16
Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan
17
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
18
Department of Biotechnology, Asia University, Taichung 413, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(7), 918; https://doi.org/10.3390/cancers11070918
Received: 25 March 2019 / Revised: 14 June 2019 / Accepted: 28 June 2019 / Published: 29 June 2019
(This article belongs to the Special Issue Hepatocellular Cancer Treatment)
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PDF [5214 KB, uploaded 3 July 2019]
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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. View Full-Text
Keywords: hepatocellular carcinoma; fisetin; protein phosphatase 1; eIF2α; chemosensitivity hepatocellular carcinoma; fisetin; protein phosphatase 1; eIF2α; chemosensitivity
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Liu, Y.-S.; Chang, Y.-C.; Kuo, W.-W.; Chen, M.-C.; Hsu, H.-H.; Tu, C.-C.; Yeh, Y.-L.; Viswanadha, V.P.; Liao, P.-H.; Huang, C.-Y. Inhibition of Protein Phosphatase 1 Stimulates Noncanonical ER Stress eIF2α Activation to Enhance Fisetin-induced Chemosensitivity in HDAC Inhibitor-resistant Hepatocellular Carcinoma Cells. Cancers 2019, 11, 918.

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