Restoring silenced suppressor gene kills lung-cancer cells

10/14/05

COLUMBUS , Ohio A new study suggests that restoring a gene often silenced in lung cancer causes the cells to self-destruct. The findings could lead to a new strategy for treating the disease.

The research focused on a gene known as WWOX, which is lost or silenced in a large majority of lung cancers, and in cancers of the breast, ovary, prostate, bladder, esophagus and pancreas. The work was led by scientists at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The study showed that both in the laboratory and in animal experiments, restoring the missing or silenced WWOX gene can slow or stop the cells' growth.

The study also showed that the reactivated gene is highly effective in stopping the growth of human lung tumors that have been transplanted into mice.

The findings are published online in the Oct. 13 Early Edition of the Proceedings of the National Academy of Sciences.

The American Cancer Society expects more than 172,500 Americans to develop lung cancer in 2005, and more than 163,500 people to die of the disease, making it the most common cause of cancer death in the U.S.

"Our findings show that restoring the WWOX gene in lung-cancer cells that don't express it will kill that lung-cancer cell," says coauthor Kay Huebner, professor of molecular virology, immunology and medical genetics and a researcher with the OSU Comprehensive Cancer Center .

"This suggests that if this gene could be delivered to, or reactivated in, the tumor cells of lung-cancer cases that are deficient in this gene, it should have a therapeutic effect."

WWOX is a tumor suppressor gene. Tumor suppressor genes safeguard the body by triggering the death of cells that have sustained serious DNA damage before the cells become cancerous. The loss or silencing of tumor suppressor genes is a fundamental cause of tumor development.

The WWOX protein is missing in cells making up many lung tumors, and in 62 percent of cases, the gene is turned off by a chemical process known as methylation.

"There is nothing wrong with those genes except that they are silenced by methylation," Huebner says. "Experimental drugs are now being tested that cause demethylation and may reactivate WWOX and other genes."

For this study, Huebner and her colleagues used three different lines of laboratory-grown lung-cancer cells that were missing WWOX protein. The researchers then used a virus engineered to carry working copies of the WWOX gene into the three cell lines.

After five days, the researchers found that cells having an active WWOX gene died off. The cells self-destructed through a natural process known as programmed cell death, or apoptosis. The lung-cancer cells that lacked the WWOX gene, on the other hand, continued growing and increased in number nearly five- or six-fold.

Next, the researchers took some of the lung-cancer cells to which they'd added working copies of the WWOX gene, and they transplanted the cells into mice; a second group of control mice received lung-cancer cells without the WWOX gene.

After 28 days, the mice that received tumor cells with no WWOX gene had developed tumors. Of the mice that received tumor cells with the gene, 60 percent in one group and 80 percent in another group showed no tumors.

"Our study is a proof of principle," Huebner says. "It shows that if the WWOX gene can be delivered into tumor cells, it can kill them.

"We also showed that if a silenced WWOX gene is present and can be turned back on, that too will kill tumor cells," adds first author and postdoctoral researcher Muller Fabbri.

"We don't believe that using WWOX as a therapy will necessarily eradicate tumors, Fabbri says, "but we do believe that this kind of gene therapy might be useful when used in combination with chemotherapy and other therapies."

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