Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

Jing Wang; Cheng Luo; Changliang Shan; Qiancheng You; Junyan Lu; Shannon Elf; Yu Zhou; Yi Wen; Jan L. Vinkenborg; Jun Fan; Heebum Kang; Ruiting Lin; Dali Han; Yuxin Xie; Jason Karpus; Shijie Chen; Shisheng Ouyang; Chihao Luan; Naixia Zhang; Hong Ding; Maarten Merkx; Hong Liu; Jing Chen; Hualiang Jiang; Chuan He

doi:10.1038/nchem.2381

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

Jing Wang, Cheng Luo, Changliang Shan, Qiancheng You, Junyan Lu, Shannon Elf, Yu Zhou, Yi Wen, Jan L. Vinkenborg, Jun Fan, Heebum Kang, Ruiting Lin, Dali Han, Yuxin Xie, Jason Karpus, Shijie Chen, Shisheng Ouyang, Chihao Luan, Naixia Zhang, Hong DingMaarten Merkx, Hong Liu, Jing Chen, Hualiang Jiang, Chuan He^*

^*Corresponding author for this work

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

90 Scopus citations

Abstract

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

Original language	English (US)
Pages (from-to)	968-979
Number of pages	12
Journal	Nature chemistry
Volume	7
Issue number	12
DOIs	https://doi.org/10.1038/nchem.2381
State	Published - Dec 1 2015

ASJC Scopus subject areas

Chemistry(all)
Chemical Engineering(all)

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Wang, J., Luo, C., Shan, C., You, Q., Lu, J., Elf, S., Zhou, Y., Wen, Y., Vinkenborg, J. L., Fan, J., Kang, H., Lin, R., Han, D., Xie, Y., Karpus, J., Chen, S., Ouyang, S., Luan, C., Zhang, N., ... He, C. (2015). Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. Nature chemistry, 7(12), 968-979. https://doi.org/10.1038/nchem.2381

Wang, Jing ; Luo, Cheng ; Shan, Changliang ; You, Qiancheng ; Lu, Junyan ; Elf, Shannon ; Zhou, Yu ; Wen, Yi ; Vinkenborg, Jan L. ; Fan, Jun ; Kang, Heebum ; Lin, Ruiting ; Han, Dali ; Xie, Yuxin ; Karpus, Jason ; Chen, Shijie ; Ouyang, Shisheng ; Luan, Chihao ; Zhang, Naixia ; Ding, Hong ; Merkx, Maarten ; Liu, Hong ; Chen, Jing ; Jiang, Hualiang ; He, Chuan. / Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. In: Nature chemistry. 2015 ; Vol. 7, No. 12. pp. 968-979.

@article{08a177f35f494411a92f994a30e3de5a,

title = "Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation",

abstract = "Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.",

author = "Jing Wang and Cheng Luo and Changliang Shan and Qiancheng You and Junyan Lu and Shannon Elf and Yu Zhou and Yi Wen and Vinkenborg, {Jan L.} and Jun Fan and Heebum Kang and Ruiting Lin and Dali Han and Yuxin Xie and Jason Karpus and Shijie Chen and Shisheng Ouyang and Chihao Luan and Naixia Zhang and Hong Ding and Maarten Merkx and Hong Liu and Jing Chen and Hualiang Jiang and Chuan He",

note = "Funding Information: This work was supported by grants from the National Natural Science Foundation of China (21210003 to H.J. and C.H., and 81230076, 91313000 to H.J.), the Hi-Tech Research and Development Program of China (2012AA020302 and 2012AA01A305 to C.L.), Chinese Academy of Sciences (XDA01040305 to C.L.), National Science Foundation (CHE-1213598 to C.H.) and National Institutes of Health (CA140515 to J.C.). C.H. is supported by the Howard Hughes Medical Institute as an investigator. We thank S. F. Reichard for help with editing the manuscript. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = dec,

day = "1",

doi = "10.1038/nchem.2381",

language = "English (US)",

volume = "7",

pages = "968--979",

journal = "Nature Chemistry",

issn = "1755-4330",

publisher = "Nature Publishing Group",

number = "12",

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Wang, J, Luo, C, Shan, C, You, Q, Lu, J, Elf, S, Zhou, Y, Wen, Y, Vinkenborg, JL, Fan, J, Kang, H, Lin, R, Han, D, Xie, Y, Karpus, J, Chen, S, Ouyang, S, Luan, C, Zhang, N, Ding, H, Merkx, M, Liu, H, Chen, J, Jiang, H & He, C 2015, 'Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation', Nature chemistry, vol. 7, no. 12, pp. 968-979. https://doi.org/10.1038/nchem.2381

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. / Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan.

In: Nature chemistry, Vol. 7, No. 12, 01.12.2015, p. 968-979.

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

TY - JOUR

T1 - Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

AU - Wang, Jing

AU - Luo, Cheng

AU - Shan, Changliang

AU - You, Qiancheng

AU - Lu, Junyan

AU - Elf, Shannon

AU - Zhou, Yu

AU - Wen, Yi

AU - Vinkenborg, Jan L.

AU - Fan, Jun

AU - Kang, Heebum

AU - Lin, Ruiting

AU - Han, Dali

AU - Xie, Yuxin

AU - Karpus, Jason

AU - Chen, Shijie

AU - Ouyang, Shisheng

AU - Luan, Chihao

AU - Zhang, Naixia

AU - Ding, Hong

AU - Merkx, Maarten

AU - Liu, Hong

AU - Chen, Jing

AU - Jiang, Hualiang

AU - He, Chuan

N1 - Funding Information: This work was supported by grants from the National Natural Science Foundation of China (21210003 to H.J. and C.H., and 81230076, 91313000 to H.J.), the Hi-Tech Research and Development Program of China (2012AA020302 and 2012AA01A305 to C.L.), Chinese Academy of Sciences (XDA01040305 to C.L.), National Science Foundation (CHE-1213598 to C.H.) and National Institutes of Health (CA140515 to J.C.). C.H. is supported by the Howard Hughes Medical Institute as an investigator. We thank S. F. Reichard for help with editing the manuscript. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

AB - Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

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U2 - 10.1038/nchem.2381

DO - 10.1038/nchem.2381

M3 - Article

C2 - 26587712

AN - SCOPUS:84947759321

VL - 7

SP - 968

EP - 979

JO - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

IS - 12

ER -

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

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