Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.118
The Endoplasmic Reticulum Stress Response Mediates Shikonin-Induced Apoptosis of 5-Fluorouracil–Resistant Colorectal Cancer Cells
Mei Jing Piao1,2,†, Xia Han1,†, Kyoung Ah Kang1,2, Pincha Devage Sameera Madushan Fernando1, Herath Mudiyanselage Udari Lakmini Herath1 and Jin Won Hyun1,2,*
1Department of Biochemistry, Jeju National University College of Medicine, Jeju 63243,
2Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
*E-mail: jinwonh@jejunu.ac.kr
Tel: +82-64-754-3838, Fax: +82-64-702-2687
The first two authors contributed equally to this work.
Received: July 14, 2021; Revised: August 26, 2021; Accepted: September 1, 2021; Published online: October 5, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil–resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box–binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil–resistant colorectal cancer.
Keywords: Naphthoquinone, 5-Fluorouracil–resistant colorectal cancer, Apoptosis, Endoplasmic reticulum stress


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