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http://dx.doi.org/10.4062/biomolther.2021.118

The Endoplasmic Reticulum Stress Response Mediates Shikonin-Induced Apoptosis of 5-Fluorouracil-Resistant Colorectal Cancer Cells  

Piao, Mei Jing (Department of Biochemistry, Jeju National University College of Medicine)
Han, Xia (Department of Biochemistry, Jeju National University College of Medicine)
Kang, Kyoung Ah (Department of Biochemistry, Jeju National University College of Medicine)
Fernando, Pincha Devage Sameera Madushan (Department of Biochemistry, Jeju National University College of Medicine)
Herath, Herath Mudiyanselage Udari Lakmini (Department of Biochemistry, Jeju National University College of Medicine)
Hyun, Jin Won (Department of Biochemistry, Jeju National University College of Medicine)
Publication Information
Biomolecules & Therapeutics / v.30, no.3, 2022 , pp. 265-273 More about this Journal
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 shikonin-induced 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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