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

J. Wang, C. Luo, Changliang Shan, Q. You, J. Lu, S. Elf, Yu Zhou, Y. Wen, J. Vinkenborg, J. Fan, H. Kang, R. Lin, D. Han, Y. Xie, J. Karpus, Sijie Chen, S. Ouyang, Chihao Luan, Naixia Zhang, Hong DingM. Merkx, Hong Liu, Jing Chen, H. Jiang, Chuan He

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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 languageEnglish
Pages (from-to)968–979
JournalNature Chemistry
Volume7
DOIs
Publication statusPublished - 2015

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Cell proliferation
Copper
Molecules
Adenosinetriphosphate
Adenosine Triphosphate
Proteins
AMP-Activated Protein Kinases
Oxidative stress
Transition metals
Tumors
Chemical activation
Cells

Cite this

Wang, J. ; Luo, C. ; Shan, Changliang ; You, Q. ; Lu, J. ; Elf, S. ; Zhou, Yu ; Wen, Y. ; Vinkenborg, J. ; Fan, J. ; Kang, H. ; Lin, R. ; Han, D. ; Xie, Y. ; Karpus, J. ; Chen, Sijie ; Ouyang, S. ; Luan, Chihao ; Zhang, Naixia ; Ding, Hong ; Merkx, M. ; Liu, Hong ; Chen, Jing ; Jiang, H. ; He, Chuan. / Inhibition of human copper trafficking by small molecule significantly attenuates cancer cell proliferation. In: Nature Chemistry. 2015 ; Vol. 7. pp. 968–979.
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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 = "J. Wang and C. Luo and Changliang Shan and Q. You and J. Lu and S. Elf and Yu Zhou and Y. Wen and J. Vinkenborg and J. Fan and H. Kang and R. Lin and D. Han and Y. Xie and J. Karpus and Sijie Chen and S. Ouyang and Chihao Luan and Naixia Zhang and Hong Ding and M. Merkx and Hong Liu and Jing Chen and H. Jiang and Chuan He",
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Wang, J, Luo, C, Shan, C, You, Q, Lu, J, Elf, S, Zhou, Y, Wen, Y, Vinkenborg, J, 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 small molecule significantly attenuates cancer cell proliferation', Nature Chemistry, vol. 7, pp. 968–979. https://doi.org/10.1038/nchem.2381

Inhibition of human copper trafficking by small molecule significantly attenuates cancer cell proliferation. / Wang, J.; Luo, C.; Shan, Changliang; You, Q.; Lu, J.; Elf, S.; Zhou, Yu; Wen, Y.; Vinkenborg, J.; Fan, J.; Kang, H.; Lin, R.; Han, D.; Xie, Y.; Karpus, J.; Chen, Sijie; Ouyang, S.; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, M.; Liu, Hong; Chen, Jing; Jiang, H.; He, Chuan.

In: Nature Chemistry, Vol. 7, 2015, p. 968–979.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

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

AU - Wang, J.

AU - Luo, C.

AU - Shan, Changliang

AU - You, Q.

AU - Lu, J.

AU - Elf, S.

AU - Zhou, Yu

AU - Wen, Y.

AU - Vinkenborg, J.

AU - Fan, J.

AU - Kang, H.

AU - Lin, R.

AU - Han, D.

AU - Xie, Y.

AU - Karpus, J.

AU - Chen, Sijie

AU - Ouyang, S.

AU - Luan, Chihao

AU - Zhang, Naixia

AU - Ding, Hong

AU - Merkx, M.

AU - Liu, Hong

AU - Chen, Jing

AU - Jiang, H.

AU - He, Chuan

PY - 2015

Y1 - 2015

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.

U2 - 10.1038/nchem.2381

DO - 10.1038/nchem.2381

M3 - Article

C2 - 26587712

VL - 7

SP - 968

EP - 979

JO - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

ER -