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Open AccessArticle

Endoplasmic Reticulum Stress-Induced Resistance to Doxorubicin Is Reversed by Mulberry Leaf Polyphenol Extract in Hepatocellular Carcinoma through Inhibition of COX-2

by Mon-Yuan Yang 1,†, Cheng-Hsun Wu 2,3,†, Tung-Wei Hung 4,5 and Chau-Jong Wang 6,7,*
1
Microbiology and Immunology, Institute of Biochemistry, Chung Shan Medical University, Taichung 402, Taiwan
2
Department of Anatomy, China Medical University, Taichung 404, Taiwan
3
Department of Biochemistry, China Medical University, Taichung 404, Taiwan
4
Department of Medicine, Division of Nephrology, Chung Shan Medical University Hospital, Taichung 402, Taiwan
5
School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
6
Department of Health Diet and Industry Management, Chung Shan Medical University, Taichung 402, Taiwan
7
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work and share first authorship.
Antioxidants 2020, 9(1), 26; https://doi.org/10.3390/antiox9010026
Received: 30 November 2019 / Revised: 19 December 2019 / Accepted: 24 December 2019 / Published: 26 December 2019
(This article belongs to the Special Issue Dietary Antioxidants in Cancer Chemoprevention)
Mulberry (Morus alba L.) leaves are used in Chinese medicine to treat metabolic disorders. Mulberry leaf polyphenol extracts (MLPE) have recently been shown to exhibit anticancer properties. Endoplasmic reticulum (ER) stress represents a pivotal obstacle in solid tumors, resulting in the antiapoptosis of tumor cells and drug resistance. In this study, pretreatment with the ER stress inducer tunicamycin (TM) attenuated the percentage of apoptosis induced by doxorubicin (DOX). Cotreatment with tunicamycin and MLPE reversed apoptosis induced by DOX. Simultaneously, induction of ER stress with tunicamycin resulted in an increased expression of Cyclooxygenase 2 (COX-2) and Glucose-regulated protein (GRP78) concomitant with the activation of p38 MAPK/PI3K/Akt in HepG2 cells. Furthermore, the suppression of ER stress with celecoxib or p38 MAPK inhibitor successfully recovered DOX-induced apoptosis. Consistent with the inhibition of COX-2 or p38 MAPK, copretreatment with TM and MLPE drastically recovered cytotoxicity and caspase-3 activation in the presence of DOX. These results reveal that MLPE reduces ER stress-induced resistance to DOX in hepatocellular carcinoma (HCC) cells through downregulation of COX-2- or p38 MAPK-mediated PI3K/Akt pathway. View Full-Text
Keywords: mulberry leaves; ER stress; drug resistance; hepatocellular carcinoma; mulberry leaf polyphenol extract mulberry leaves; ER stress; drug resistance; hepatocellular carcinoma; mulberry leaf polyphenol extract
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Yang, M.-Y.; Wu, C.-H.; Hung, T.-W.; Wang, C.-J. Endoplasmic Reticulum Stress-Induced Resistance to Doxorubicin Is Reversed by Mulberry Leaf Polyphenol Extract in Hepatocellular Carcinoma through Inhibition of COX-2. Antioxidants 2020, 9, 26.

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