Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer

Weishan Zhuge; Ruijie Chen; Katanaev Vladimir; Xidan Dong; Khan Zia; Xiangwei Sun; Xuanxuan Dai; Miao Bao; Xian Shen; Guang Liang

doi:10.1016/j.canlet.2017.10.006

Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer

Weishan Zhuge, Ruijie Chen, Katanaev Vladimir, Xidan Dong, Khan Zia, Xiangwei Sun, Xuanxuan Dai, Miao Bao, Xian Shen, Guang Liang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

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.

Original language	English
Pages (from-to)	46-58
Number of pages	13
Journal	Cancer Letters
Volume	412
DOIs	https://doi.org/10.1016/j.canlet.2017.10.006
Publication status	Published - 1 Jan 2018
Externally published	Yes

Keywords

Colon cancer
Costunolide
Endoplasmic reticulum stress
Oxidative stress
Thioredoxin/thioredoxin reductase 1

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10.1016/j.canlet.2017.10.006

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title = "Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer",

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.",

keywords = "Colon cancer, Costunolide, Endoplasmic reticulum stress, Oxidative stress, Thioredoxin/thioredoxin reductase 1",

author = "Weishan Zhuge and Ruijie Chen and Katanaev Vladimir and Xidan Dong and Khan Zia and Xiangwei Sun and Xuanxuan Dai and Miao Bao and Xian Shen and Guang Liang",

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year = "2018",

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doi = "10.1016/j.canlet.2017.10.006",

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T1 - Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer

AU - Zhuge, Weishan

AU - Chen, Ruijie

AU - Vladimir, Katanaev

AU - Dong, Xidan

AU - Zia, Khan

AU - Sun, Xiangwei

AU - Dai, Xuanxuan

AU - Bao, Miao

AU - Shen, Xian

AU - Liang, Guang

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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KW - Costunolide

KW - Endoplasmic reticulum stress

KW - Oxidative stress

KW - Thioredoxin/thioredoxin reductase 1

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SN - 0304-3835

VL - 412

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JO - Cancer Letters

JF - Cancer Letters

ER -

Costunolide specifically binds and inhibits thioredoxin reductase 1 to induce apoptosis in colon cancer

Abstract

Keywords

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