Protein Induces Ovarian Cancer Cells To Consume Themselves

A protein known to suppress the growth of ovarian cancer has been found to work partly by forcing cancer cells to consume themselves until they die.

Researchers from The University of Texas M.D. Anderson Cancer Center (Houston, TX, USA) reported their findings in the November 15, 2008, issue of the journal Cancer Research. They also found that expression of the protein, known as phosphoprotein enriched in astrocytes-15 (PEA-15), is an independent indicator of a woman's chances for surviving ovarian cancer, according to senior author Naoto T. Ueno, M.D., Ph.D., associate professor of breast medical oncology.

An analysis of ovarian cancer tumors from 395 women revealed those with high expression of the PEA-15 had an average survival time of 50.2 months compared with 33.5 months for women with low levels of the protein in their tumors. "These findings provide a foundation for developing a PEA-15-targeted approach for ovarian cancer and for clarifying whether this protein is a novel biomarker that can predict patient outcomes," Dr. Ueno stated.

Ovarian cancer kills approximately 15,000 women in the United States annually, and is extremely hard to diagnose in its early stages, when it is most optimal to treat.

A series of lab experiments by first author Chandra Bartholomeusz, M.D., Ph.D., demonstrated that high expression of PEA-15 inhibits the growth of ovarian cancer cells by killing cells via autophagy, or self-cannibalization, rather than by apoptosis. Removing PEA-15 from ovarian cancer cells led to a 115% increase in the number of cells compared with a control group of cells that still had the protein.
In apoptosis, defective cells die from self-induced damage to their nuclei and DNA complex. Autophagy kills when a cell entraps parts of its cytoplasm in membranes and digests the contents, leaving a cavity. When this goes on long enough, the cell fundamentally eats itself until it dies, its cytoplasm riddled with cavities.

Dr. Ueno's research team has found that the protein works to suppress cancer in two distinct ways depending on its location in the cell. First, PEA-15 inhibits one of the prominent actors in the growth, differentiation, and mobility of cells, a protein called extracellular signaling related kinase (ERK). Activated ERK in the cell nucleus promotes cancer growth. The researchers earlier discovered that PEA-15 binds to ERK in the nucleus and moves it out into the cytoplasm, preventing its growth effects.

Now, the investigators found that PEA-15 in the cytoplasm induces autophagy in cancer cells, a second method of inhibiting cancer growth. "These two very different actions by PEA-15 are based on the location of the protein," Dr. Ueno said.

ERK is an inviting target for cancer therapy, Dr. Ueno noted, but so far, no one has been able to develop an effective ERK inhibitor. "PEA-15 offers us a new dimension for potentially targeting ERK. We've shown with high levels of PEA-15, women with ovarian cancer are surviving longer." Levels of the protein in tumors also might affect how other drugs work against the disease. Similar research is under way in breast cancer with the protein.

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M.D. Anderson Cancer Center