Achilles' Heel for Cancer

After a Seven Year Search, A Key Enzyme Is Discovered in Yeast Which May Bring a Promising Cancer Therapy

by Kathleen Scalise

A discovery that points to a promising new approach for stopping the growth of cancerous tissue was announced by Berkeley and Acacia Biosciences, Inc. researchers in the March 21 issue of Science.

The researchers have found an enzyme that when eliminated from cancer-like cells in yeast returned the cells to near normal activity.

"It looks very promising for cancer therapy, but we don't know yet how it will work in humans," said Matthew Ashby, who with Molecular and Cell Biology Professor Jasper Rine and researcher Victor Boyartchuk made the finding, after searching nearly seven years.

The researchers are hopeful their findings will eventually result in more effective anticancer treatments, perhaps a new form of chemotherapy, for many types of cancer.

The enzyme they identified interacts with an important molecular switch -- the protein from the cancer-causing oncogene called ras. Ras is the second most prevalent oncogene in humans.

Mutated forms of ras have been implicated in a wide range of cancers.

"Ras has been the focus of much scientific research because of its role in cancers that are difficult to treat," said Ashby.

"For example it has been implicated in colon, lung, pancreatic and liver cancer."

In many organisms, including humans, ras transmits signals telling the cell whether or not to divide.

Mutated ras locked into the "on" position can cause unstoppable cell division resulting in cancer.

The discovered enzyme, Rce1, clips a portion off the ras protein -- both mutant and regular varieties -- allowing it to move into position near the cell membrane and begin transmitting signals for cell division.

When the researchers interfered with this process by genetically removing the enzyme, ras activity plummeted.

"Here was an Achilles' heel to ras," said Ashby.

"Furthermore, it looked like the mutant form of ras was more susceptible to the loss of Rce1 than was the normal form.

"This has broad implications for the development of drugs that will inhibit cancer cells, but leave normal cells alone."

The irony is that although mutated forms of the ras protein can lead to cancer, organisms cannot survive without ras.

Experimental cancer therapies targeted at ras must therefore knock out some of its function, but not all.

This balance is what the researchers hope might one day be achieved by blocking Rce1, which reduces but does not eliminate ras function, at least in yeast cells.

Determining the enzymatic mechanism of Rce1 will be critical to developing potent inhibitors.

Yet this information has been impossible to obtain from in vitro experiments or even from the primary structure of the gene.

Scientists believe there are only four classes of such protease enzymes. But Rce1 matches none of the known types.

The yeast ras protein on which the researchers worked is very similar to the human variety, said Ashby. So the researchers are hopeful their findings will hold true across the two species.

They are now looking for the same type of enzyme activity in human cells and hope to have findings soon.

Ras "is found in just about all organisms," said Ashby.

"It's in yeast, worms, fruit flies and all mammals, including humans. It has different functions in different cell types, but it's always a signal to divide."

A Berkeley post-doctoral researcher working with Rine when the project began, Ashby is now director of biology for Acacia Biosciences, a company based in Richmond, Calif., which formed to commercialize genomic-based drug discovery technology developed by Rine, Ashby and others.


Copyright 1997, The Regents of the University of California.
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