Molecular "Handbrake" Could Be Released To Send Cancer Cells To Their Death

The pharmacologists believe it might be possible to develop drugs to "release" the Pin1 handbrake in cancer cells treated with radiation or chemotherapy - causing the cancer cells to rush recklessly into dividing despite having lethally damaged DNA. Thus, they say, drugs inhibiting Pin1 might prove powerful, targeted enhancers of therapies for a wide array of cancers.

The researchers reported their findings in the March 3 issue of Science. They are graduate student Katharine Winkler, Assistant Research Professor Katherine Swenson, Assistant Professor Sally Kornbluth, and Professor and Chairman Anthony Means, all of the medical center department of pharmacology and cancer biology. Their research is sponsored by the National Institutes of Health, Glaxo Wellcome and the American Cancer Society.

In their research, the scientists studied the effects of Pin1 depletion in extracts of frog eggs that allowed them to pinpoint where in the cell division cycle the enzyme exerted its influence. They found that the enzyme-deficient extracts entered the cell division process early. In fact, the Pin1-deficient extracts proceeded through cell division despite being exposed to chemicals that inhibited DNA replication. The scientists also found that adding back active Pin1 enzyme to these extracts restored the normal controls.

However, when they added back a "crippled" version of Pin1, exactly like normal Pin1 except it was lacking in enzymatic activity, the checkpoint controls were not restored.

The key to Pin1's potential importance in cancer treatment lies in the fact that the majority of cancers are already defective in another critical brake on their growth, called p53, Means said.

"It's like having the regular brake on a car rendered inoperable, which makes this second brake really important," he said. Defective p53 is critical to enabling cancer cells' malignant growth, because it allows the cells to escape the normal controls on cell division, said Means. However, cancer cells' lack of p53 also raises the potential of using Pin1-inhibiting drugs to trigger cancer cells to divide and die even with DNA severely damaged by radiation or chemotherapy. Fortunately, such anti-Pin1 treatment would tend to spare normal cells from uncontrolled division, Means said.

"While p53-defective cancer cells have only one brake, normal cells still have functional p53, so treatment with Pin1 inhibitors should have far less impact on them," he said. Also, said Means, since Pin1 is found in all cells, it is also present in a wide array of cancers."If a therapeutic is to come out of this finding, it would likely be a general therapeutic for cancers, not just for leukemias, prostate cancer or breast cancer," he said. "It could be a broadly applicable ancillary agent for combination therapies for many cancers."

Pin1 is a well-understood molecule, Means added, and screening drugs to find those with specific anti-Pin1 activity should be quite feasible.

The research team's next step after their studies in frog eggs will be to extend their findings to confirm the regulatory role of Pin1 in mammals such as mice, so that they can progress to a search for Pin1-inhibiting drugs. The researchers also plan to study an array of tumors to explore whether lack of p53 does, indeed, increase levels of protective Pin1 in those tumors - thus rendering the tumors vulnerable to Pin1 inhibitors. The scientists also will seek to understand in detail Pin1's function in cell division.

"We still don't specifically understand what Pin1 does," Means said. "It may have a chaperone function in helping cell cycle control molecules reach the right place in the cell, but we also know that it binds many different proteins in the cell, indicating that it likely has many functions."