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Inhibition of human copper trafficking significantly attenuates tumor growth
Update time: 2015-11-10
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Copper is a trace element that is required by almost all forms of life. Acting as cofactors for various key metabolism enzymes, copper takes part in many vital biological processes. Previous studies have found the concentration of copper is significantly higher in tumor cells than in normal cells. In addition, copper can promote angiogenesis by activating VEGF and FGF signaling. A recent paper on Nature revealed that copper is essential for oncogenic BRAF signaling and tumorigenesis. These studies suggest copper metabolism could be a promising target to treat cancer.

Currently, the only way to regulate intracellular copper level is to use chelating agents, such as Tetrathiomolybdate (TTM). Through chelating copper ions, TTM reduce the concentration of cellular copper and has been used to treat diseases caused by excess copper, such as Wilson's disease. TTM can also inhibit angiogenesis and show anti-cancer activities. Unfortunately, most chelating agents, including TTM, show very poor selectivity among cations, and therefore exhibit severe side-effects in clinical use. 

Through combining computational and experimental approaches, Prof.JIANG Hualiang’s group from Shanghai Institute of Materia Medica, Prof.HE Chuan’s group from Chicago University and Prof.CHEN Jing’s group from Emory University identified a series of compounds that could regulate cellular copper signaling by targeting copper trafficking protein Atox1 and hCCS. Structural based virtual (in silico) screening was firstly used to identify small molecules that target the copper transfer interface of Atox1 and hCCS. Subsequent biochemical experiment validated that several compounds could bind to Atox1 and CCS. Among them, DCAC_50 and DCAC_2 showed the highest binding affinity. In addition, mutagenesis studies confirmed the binding mode predicted by in silico modeling. Cellular assays showed that these compounds exhibit dose-dependent inhibitory activities on the proliferation of cancer cells, through increasing cellular ROS level and inhibiting ATP synthesis. Most importantly, one of these compounds, DCAC_50, also showed prominent anti-tumor activities on animal models without toxicities.  

Thomas O’Halloran of Northwestern University, who has studied tetrathiomolybdate, comments that “the challenge in drug design is hitting one of these copper-dependent processes without messing with housekeeping functions that normal cells depend upon. DC_AC50 appears to block the function of copper metallochaperone proteins without interacting directly with their cargo, copper ions. As the first member of a new class of inhibitors, it provides a new way to interrogate the physiology of copper trafficking disorders and possibly intervene.”

This study has been published online on Nature Chemistry in Nov 9th, 2015. DCAC_50 has also got an international patent and is under pre-clinical evaluation currently. This work was supported by grants from Chinese Academy of Sciences, Ministry of Science and Technology of China, and the National Natural Science Foundation of China. 

Abstract:

Copper is a transition metal that plays critical roles in many important life processes. We report here small molecules that inhibit the human copper trafficking proteins Atox1 and CCS, providing an approach to selectively disrupting cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to significantly reduced proliferation of cancer cells but not normal cells, as well as attenuated tumor growth in mouse models. We found that blocking of copper trafficking induces cellular oxidative stress (ROS) and reduces the cellular ATP level; the reduced ATP level results in activation of 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 anticancer therapeutic developments.

Through binding to Atox1 and CCS and disrupting copper trafficking, DC_AC50 increases cellular ROS level and inhibits ATP synthesis, which eventually leads to the proliferation inhibition of cancer cells.(Image by SIMM)

Correspondence:Hualiang Jiang, Tel: +86-21-50806600/1303

E-mail: hljiang@simm.ac.cn

Original article: http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2381.html

 
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