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

• Published in: Nature chemistry Vol. 7; no. 12; pp. 968 - 979
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2015; Nature Publishing Group
• Subjects: 119/118; 639/638/45/49/1141; 639/638/92/507; 639/638/92/555; 639/638/92/556; Amino Acid Sequence; Analytical Chemistry; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP; Biochemistry; Cancer; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry/Food Science; Copper; Copper - metabolism; Drug Discovery; Gene Knockdown Techniques; Humans; Inorganic Chemistry; Kinases; Metallochaperones - antagonists & inhibitors; Metallochaperones - chemistry; Metallochaperones - genetics; Metallochaperones - metabolism; Mice; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - chemistry; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Molecular Sequence Data; Neoplasms - metabolism; Organic Chemistry; Oxidative stress; Oxidative Stress - drug effects; Physical Chemistry; Proteins; Sequence Alignment; Xenograft Model Antitumor Assays; United States > US; Illinois; Chicago Illinois
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2381

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.
Copper is a transition metal ion essential for the regulation of cellular oxidative stress and ATP production. Now, the inhibition of copper-trafficking proteins by a small molecule has been shown to significantly reduce proliferation of cancer cells. The results indicate that copper-trafficking proteins could represent new anti-tumour therapeutic targets.