Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer. (1st January 2018)

• Record Type: Journal Article
• Authors: Zhuge, Weishan; Chen, Ruijie; Vladimir, Katanaev; Dong, Xidan; Zia, Khan; Sun, Xiangwei; Dai, Xuanxuan; Bao, Miao; Shen, Xian; Liang, Guang
• Is Part Of: Cancer letters. Volume 412(2018)
• Page Start: 46
• Page End: 58
• Publication Date: 2018-01-01
• Subjects: Colon cancer -- Costunolide -- Thioredoxin/thioredoxin reductase 1 -- Oxidative stress -- Endoplasmic reticulum stress; ER endoplasmic reticulum -- TrxR1 thioredoxin/thioredoxin reductase 1 -- EIF2 eukaryotic initiation factor 2 -- ATF-4 activating transcription factor 4 -- CHOP CAAT/enhancer-binding protein homologous protein -- PI propidium iodide -- DCFH-DA 20, 70-dichlorodihydrofluorescein diacetate -- MDM-2 murine double minute 2 -- Cdc2 cyclin-dependent kinase 1 cell division cycle protein 2 -- PARP poly ADP-ribose polymerase -- NAC N-acetyl cysteine -- MTT 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- Ki-67 nuclear protein associated with cell proliferation -- MDA malondialdehyde; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.10.006
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Colon cancer is one of the leading causes of cancer-related deaths. A natural sesquiterpene lactone, costunolide (CTD), showed inhibition of cancer development. However, the underlying mechanisms are not known. Here, we have examined the therapeutic activity and novel mechanisms of the anti-cancer activities of CTD in colon cancer cells. Using SPR analysis and enzyme activity assay on recombinant TrxR1 protein, our results show that CTD directly binds and inhibits the activity of TrxR1, which caused enhanced generation of ROS and led to ROS-dependent endoplasmic reticulum stress and cell apoptosis in colon cancer cells. Overexpression of TrxR1 in HCT116 cells reversed CTD-induced cell apoptosis and ROS increase. CTD treatment of mice implanted with colon cancer cells showed tumor growth inhibition and reduced TrxR1 activity and ROS level. In addition, it was observed that TrxR1 was significantly up-regulated in existing colon cancer gene database and clinically obtained colon cancer tissues. Our studies have uncovered the mechanism underlying the biological activity of CTD in colon cancer and suggest that targeting TrxR1 may prove to be beneficial as a treatment option. Highlights: ROS accumulation and ER stress contribute to CTD-mediated apoptosis. CTD binds and inactivates TrxR1 activity to induce ROS and cell apoptosis in colon cancer. TrxR1 is up-regulated in colon cancer and may be a potential target. CTD may is a therapeutic approach to treating colon cancer by inhibiting TrxR1.