title: Dihydroartemisinin-Induced Apoptosis is Associated with Inhibition of Sarco/Endoplasmic Reticulum Calcium ATPase Activity in Colorectal Cancer.
abstract: Dihydroartemisinin (DHA) is a promising anti-cancer compound capable of inhibiting proliferation and inducing apoptosis of various cancer cells, including colorectal cancer. However, the molecular mechanisms have not been well understood. This study aimed to explore the underlying mechanism of DHA-induced apoptosis in HCT-116 cells. Cell counting kit-8 assay and flow cytometry analysis confirmed that DHA inhibited proliferation, arrested cell cycle at G0/G1 phase, and enhanced apoptosis in HCT-116 cells. Fluo-3/AM-stained flow cytometry assay revealed that the intracellular Ca(2+) concentration of HCT-116 cells was increased significantly after DHA treatment. Meanwhile, the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA) was appeared to be reduced in a dose-dependent manner. We further detected the upregulated expression of CAAT/enhancer binding protein homologous protein (CHOP) in DHA-treated HCT-116 cells. Conversely, silencing CHOP resulted in a decrease of DHA-induced apoptosis. In addition, the expression of Bax in cytoplasm was elevated significantly along with the sharply decline of Bcl-2 expression in DHA-treated HCT-116 cells. Moreover, the distributions of Bid on mitochondria were increased, accompanied by the activation of caspase-3 in the presence of DHA. Overall, our data indicated that DHA triggered endoplasmic reticulum (ER) stress through inhibiting SERCA activity to release intracellular Ca(2+) from ER, the upregulated expression of CHOP activated mitochondrial apoptosis pathway to induce apoptosis of HCT-116 cells. Therefore, our findings provide a theoretical foundation for DHA as a potential candidate in treatment of colorectal cancer.
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China. minlu1@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Seven-Year System, Department of Clinical Medicine, China Medical University, Shenyang, 110001, People's Republic of China.
authors.forename: Luhaoran
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Colorectal Surgery, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang, 110013, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Experimental Center for Functional Subjects, College of Basic Medical Sciences, China Medical University, Shenyang, 110013, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
mesh_terms: D017209:Apoptosis; D037621:Artemisinins / Q000633:toxicity; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D015179:Colorectal Neoplasms / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D037621:Artemisinins; D022762:CCAAT-Enhancer-Binding Proteins; C039060:artenimol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Colorectal cancer; Dihydroartemisinin; Endoplasmic reticulum stress; Mitochondrial apoptosis pathway; Sarco/endoplasmic reticulum calcium ATPase