Neurological Disorder

Cancer Pathways

Cancer Research

Biology in the Basement
Research Briefs
Around & About
POV


When the "guardian" protein of the cell, p53, gets the message that a cell would rather die than put up with the stress it's experiencing, p53 enacts the cell's suicide plan. Suicide sounds bad, but is actually a good option for an organism with DNA-damaged cells that might otherwise evolve into a mass of cancer.

Most cancer drugs try to take advantage of the suicide option by boosting the killing activity of p53 in tumor cells. But the drugs are surprisingly ineffective in some cancers with p53 proteins that appear fully capable of inducing death. In some of these stubborn cancers, the p53 proteins are stuck in the cytoplasm and are unable to migrate to the nucleus where the suicide plan is put into motion.

In a finding that could lead to new therapies for such intractable cancers, the molecule responsible for sequestering p53 in the cytoplasm has been identified by Dr. Wei Gu, assistant professor of pathology in the Institute for Cancer Genetics, and his graduate student Anatoly Nikolaev. The two researchers also found they can make some hard-to-treat cancers vulnerable to chemotherapy by reducing the amount of the new molecule, called Parc, in the cancer cells. The research was published in the Jan. 10 Cell.

For 20 years, researchers have hypothesized that p53 must be held in the cytoplasm by an anchor protein until p53 is needed in the nucleus. But it was difficult to identify an anchor protein because p53 killed cells before biochemists could recover candidate molecules.

To get around the cell death problem, Dr. Gu and Mr. Nikolaev cultured human cells with a mutant form of p53 that couldn't kill. From these cells, they identified a previously unknown protein attached to p53 in the cytoplasm. They named the protein Parc, for its sequence similarity to Parkin, a protein involved in Parkinson's disease.

To find out what Parc does, the researchers changed the amount of Parc inside human cells, producing cells with little Parc and cells with too much Parc. Both lines of cells had normal p53 protein. In Parc-free cells, p53 proteins migrated into the nucleus and half the cells died from p53-directed suicide. Conversely, in cells with excess Parc, almost all the p53 remained in the cytoplasm. The results showed that Parc keeps p53 in the cytoplasm until p53 is needed in the nucleus.

Because the cells with extra Parc hold p53 in the cytoplasm as some resistant cancers do, Dr. Gu and Mr. Nikolaev determined whether cancers also contain excess Parc. The results—neuroblastomas had 10 times more Parc than normal cells—suggest that reducing Parc, or keeping it from binding p53, could be therapeutic.

But when they reduced the level of Parc in the cancer cells—using RNA interference, a method that employs an RNA that binds to a target mRNA (in this case Parc mRNA) and leads to its destruction—few cells died. The researchers saw greater killing when they combined a chemotherapy drug etoposide with Parc reduction via RNA interference. With the combination, more than 50 percent of the cancer cells died.

For patients, Dr. Gu says preventing Parc from binding p53 is more feasible than trying to reduce its concentration in cancer cells. His lab is now looking to screen small molecules that can block the interaction between Parc and p53 to find potential drugs that could make chemotherapy more effective in patients with neuroblastoma and other intransigent cancers. They are also looking at the levels of Parc in other cancers that have resisted chemotherapy. Columbia has applied for a patent on Parc and applications of its potential uses.

"We're excited," Dr. Gu says. "Since our results show that inactivating Parc can sensitize tumor cells to chemotherapy drugs, we think Parc may prove to be a very important target for cancer therapy."

The work was supported in part by grants from the Avon Foundation, the Irma T. Hirschl Trust, and the National Cancer Institute. Dr. Gu also is a Leukemia & Lymphoma Society Scholar.


[Top]