New understanding of ‘copper pump’ in cells could prime discovery of anti-cancer drugs

19 May 2012

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A team of University of California, San Diego, researchers has made new discoveries about a copper-transporting protein in the membranes of human cells that drug-discovery scientists can co-opt for the development of new anti-cancer drugs.

The findings, published on 9 May 9 an online-first paper in Cell Biochemistry and Biophysics, describe how the copper transporter works as a biochemical pump to seize copper atoms outside of a cell and whisks the atoms through the otherwise impervious cell membrane into the cell cytoplasm. The same pump transports the platinum-containing drug cisplatin into cancer cells to help kill them. Igor Tsigelny, a research scientist at the university's San Diego Supercomputer Centre and Department of Neurosciences, is lead author of the paper.
 
The body needs only a tiny amount of copper, but the little that is needed acts as a key component of vital cellular enzymes, including superoxide dismutase, cytochrome c oxidase, lysyl oxidase and dopamine ß-hydrolase.

Researchers have shown before that that human copper transporter 1 (hCTR1) protein also participates in transport of the platinum-containing cisplatin, one of the most widely used anti-cancer drugs. Once platinum-containing cisplatin molecules enter a tumour cell, the molecules interact with the cell's DNA and kill it in a process that has been extensively studied by Stephen B. Howell, a professor of medicine at the UC San Diego Moores Cancer Center.

The way that hCTR1 works is a focus of research by Howell and other cancer researchers because cisplatin and similar drugs somehow lose their punch: they are effective anti-cancer drugs when first administered, but lose much of their effectiveness during cancer relapses. Some researchers theorise that the diminished effect of cisplatin could be due to a change in hCTR1 in cancer cells.

New insights derived by the UC San Diego team is leading to a better understanding of what happens to the protein transporter and that knowledge could possibly be used to design a better version of cisplatin or an entirely new drug to take advantage of the new information.

In addition to cancer researchers, the hCTR1 has been a mystery to cell biologists. Until recently, they didn't know whether the transporter protein formed dimers, or trimers. In a 2006 breakthrough that was refined in 2009, scientists confirmed that the trimer is the predominant structure, which was confirmed by the pioneering work of Northwestern University Professor Vincenz Unger.
 
Unger's team identified the structure of the part of the hCTR1 transporter protein that spans the cell membrane. But they were not able to determine the structure of the part of the protein that extends to the outside of the membrane. Because of that gap in knowledge, they were not able to obtain a high-resolution 3-D map of the protein's structure.

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