Switching the suicide protein back on

Dr Don Tindall and Dr Haojie Huang were conducting research on prostate cancer at Tindall's lab in Rochester. They were studying cancer cell behavior after treatment. Tindall says typically advanced prostate cancer is treated by castration. It's radical, but, initially, very effective.

"Most of the patients respond very favorably to this type of treatment. However, after a period of time these tumors recur, inevitably," Tindall says.

A cell kind of gets to a point where it says, 'Okay so far so good, should I continue?' And there are certain sentinels standing guard so that a cell asks the sentinels such as CDK2 whether it can proceed or whether it should stay there.

The researchers couldn't figure out why the cancer cells came back, because the body makes prostate cells with a very specific and naturally occurring steroid. Removing the prostate gets rid of that steroid, which should starve the cancer. But Tindall says the cells react with a Darwinian drive for survival.

"It either dies or it generates some survival mechanism," Tindall explains. "And many of them die, of course, but a few cells are smart enough to develop these other survival mechanisms."

That brings us to the life of a call.

Take a cell, any cell. In time, it wants to become two cells. So it creates a copy of itself inside the cell, and then it divides. But it will only do this if the cell is healthy. And that's where we get to meet CDK2. That's the name researchers like Tindall gave to a protein that is vital to this process.

"A cell kind of gets to a point where it says, 'Okay so far so good, should I continue?' And there are certain sentinels standing guard so that a cell asks the sentinels such as CDK2 whether it can proceed or whether it should stay there," Tindall says.

If CDK2 decides the cell shouldn't split it tells the cell to hold on. And sends a message to a protein with another catchy name, FOX01. It's a little like a secret message folded up and passed along, one protein to the next until finally FOX01 fires off its own note, cell: you must self-destruct.

In a non-cancerous cell these proteins work pretty well.

But researchers found the suicide protein wasn't telling prostate cancer cells to die, which meant the sentinel protein CDK2 wasn't working.

Researchers had already figured out that prostate cancer cells had changed their genetic makeup in order to survive without the needed steroid. That meant the cancer cells were also preventing FOX01 from working, otherwise they'd be dead. But how? Tindall says Huang figured out that the sentinel protein CDK2 communicated with FOX01.

"So by looking at the protein, looking at it every which way, he found this unique sequence," Tindall says. "And no one had ever connected CDK2 with FOX01."

This simple discovery is critical. Researchers then learned that the prostate cancer cell had mutated the sentinel protein. So the sentinel gave bad instructions to the suicide protein. Essentially, the cancer cells were avoiding the self-destruct message.

Dr. James McCarthy is a professor at the University of Minnesota Cancer Center, where Haojie Huang now works. He says the study's findings are fairly simple, but they took a lot of work. McCarthy says now that they know there is a connection, they can apply it to other cancers.

"Certainly this mechanism would occur in other cells, or this checkpoint would occur in other cells," McCarthy says. "The question is are tumor cells from other cancers, do they have the same sort of defect? And this certainly can be tested."

McCarthy says the findings, published in the journal Science, will also allow researchers to develop drugs that target the very protein that's malfunctioning.

"I mean in the long term in cancer treatment, ideally one of the notions is that therapy will be tailored to patients, this is very long term of course. But if you know what pathways are defective then you could give the appropriate drug to that patient and improve their response," he says.

That would mean after removing a cancer, patients would have a better chance of full-remission because the drugs would, hopefully, ensure there were no rogue cancer cells mutating their way into survival.

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