Biology Breakthrough Could Aid Understanding of Cancer

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CORVALLIS, Ore. – Researchers have made a fundamental advance in the understanding of cell biology that helps to explain how cells in higher organisms, including humans, send out signals that control cell division, cell death and other key functions.

The discovery should open new avenues to research on cancer, the scientists said.

The new study, to be published Friday in the journal Science by biochemists from Oregon State University and Wake Forest University, may also help resolve a significant debate in the science community about the role of hydrogen peroxide in cellular signaling and control of life processes.

This chemical would be recognized by most people as a common disinfectant found in the family medicine cabinet, used to cleanse wounds or a kitchen countertop.

But the new study provides strong evidence for how hydrogen peroxide is able to signal cells to divide, differentiate, or even commit suicide. These biochemical functions are essential to human life, and if they are dysfunctional may lead to cancer – which, from a simple perspective, is uncontrolled cell division.

“Hydrogen peroxide, like some other oxidative molecules, is usually a toxin we’re trying to get rid of,” said Andrew Karplus, a professor of biochemistry at OSU. “In most cases it’s an unnecessary byproduct that results from our processing of oxygen, which we need to live. And there is a considerable community of scientists who believe that’s about all it is, a toxin that needs to be eliminated.”

But another group of researchers, Karplus said, point to a wide range of evidence that hydrogen peroxide plays a key role in cellular signaling and communication – a switch, in a way, that’s only flipped on rare occasion but is critical to such cellular processes as division and programmed cell death. It’s never been clear, however, exactly how the same chemical can be both an unwanted toxin and a chemical that’s literally essential to the survival of higher life forms.

The newest findings, Karplus said, appear to answer that question.

In this research, the scientists were studying the function of peroxiredoxin, an enzyme whose primary task in a wide range of plant, animal and even bacterial life forms appears to be the detoxification of hydrogen peroxide.

The new discovery started out as purely basic research, Karplus said – the OSU and Wake Forest researchers were trying to model the atomic structure of peroxiredoxin from salmonella bacteria, as part of their programs in protein crystallography and understanding the basic biochemical processes of life.

They found that the peroxiredoxin from bacteria does a great job of detoxifying hydrogen peroxide, keeping it from killing cells. But when the scientists then compared the peroxiredoxin from bacteria with that from humans, they found that the enzyme from humans was larger and, for some reason, appeared only to be able to detoxify low levels of hydrogen peroxide – larger amounts of hydrogen peroxide would overwhelm the peroxiredoxin and kill it. What they discovered was that the extra size of peroxiredoxin molecule in humans causes it to work a little more slowly, and that makes in vulnerable to being killed.

“This was really pretty strange,” Karplus said. “There’s not a lot of biological precedent for an enzyme that exists primarily to get rid of another molecule, but when too much of that molecule exists, the enzyme itself becomes the victim. In humans, depending on the levels of these two compounds, this is a little dance of death in which sometimes the hydrogen peroxide is the winner.”

But the fact that hydrogen peroxide can actually survive, and even overwhelm the compound that exists to detoxify it must have evolutionary value, the researchers believed. They hypothesized that this adaptation allows the peroxiredoxin to act much like a floodgate would, keeping resting levels of hydrogen peroxide low, while permitting higher levels to flow throughout the cell to perform their signaling function.

“What we now understand, in other words, is how hydrogen peroxide could function in mammals and other higher life forms both as a toxin and a signal,” Karplus said. “In our bodies, hydrogen peroxide appears to be part of the mechanism that induces cell death at appropriate times – for instance, in cancer cells when they are attacked by our immune system.”

Some anti-cancer drugs, such as cisplatin, actually function by causing more hydrogen peroxide to be made in cells, Karplus said. And some cancer cells that are resistant to cisplatin or other forms of cancer therapy such as radiation appear to be making larger amounts of peroxiredoxin.

The findings that emerged from this basic research program could have immediate value to suggest new types of cancer research, Karplus said, and eventually therapies.

This research was supported by the National Institutes of Health and the American Heart Association.

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