Cell Enzyme May Help Suppress Cancer Development

The enzyme is known as PTPRO (for "protein tyrosine phosphatase receptor-type O"). When the gene responsible for producing PTPRO is silenced, as can happen in lung cancer, for example, the amount of the enzyme drops, allowing the cells to grow when they shouldn't.

The research, led by investigators at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, may offer a new target for cancer therapy and may lead to new ways to diagnose some cancers and determine a patient's prognosis and response to treatment.

The findings were published in a recent issue of the Proceedings of the National Academy of Sciences.

"This appears to be the first report of an enzyme also serving as a tumor suppressor," says study leader Samson T. Jacob, William C. and Joan E. Davis Professor in cancer research and professor of molecular and cellular biochemistry and internal medicine. "It shouldn't come as a surprise, however, because of the nature of this enzyme."

PTPRO removes phosphate groups from the amino-acid tyrosine found in specific proteins. Some proteins become activated and some become inactivated when phosphate groups are removed. It is likely that the silencing of PTPRO alters the phosphate levels of some of these proteins and helps initiate processes that lead to cancer.

In this study, Jacob and his colleagues show that the PTPRO gene is silenced gradually by a process known as methylation. Methylation causes the addition of small chemical units known as methyl groups to a gene. As methyl units accumulate on a gene, the gene become less active and fewer copies of its protein are made.

In this case, silencing of the PTPRO gene causes a drop in the level of the PTPRO enzyme. That, in turn, affects certain proteins that PTPRO acts on, furthering the cancer process. When the loss or silencing of a gene contributes to cancer, the gene is called a tumor-suppressor gene. That is, the normal activity of the gene suppresses cancer development.

xamined the PTPRO gene for methylation in 43 primary human lung tumors and their matching normal adjacent tissue. Fifty-one percent of the tumor samples were heavily methylated, while the gene in the adjacent normal tissue was essentially methylation-free.

When the researchers modified laboratory-grown human lung-cancer cells to over-produce the PTPRO enzyme, they showed that the cells proliferated more slowly and more often died from programmed cell death -- apoptosis

In addition, when the researchers used a chemical to remove the methylation in a cancer-cell line, it slowed the growth of the cells, again suggesting that the presence of the PTPRO gene and its enzyme slowed the cancer process.

Taken together, the evidence strongly suggests that the PTPRO gene is a tumor suppressor gene. If further research verifies the importance of the PTPRO gene to the cancer process, it may mean that measuring the degree of methylation of this gene in a patient's tumor will tell doctors something about the level of danger posed by that tumor or whether the tumor is responding well to treatment.

Jacob and his colleagues are now working to identify the proteins that the PTPRO enzyme interacts with, and they are analyzing samples from a wide range of cancers to learn which ones also show silencing of the PTPRO gene.

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Other OSU researchers involved in this study were Tasneem Motiwala, senior research associate in molecular and cellular biochemistry; Huban Kutay, research associate in molecular and cellular biochemistry; Kalpana Ghoshal, research scientist in molecular and cellular biochemistry; Shoumei Bai, graduate research associate in molecular and cellular biochemistry; Saul Suster, professor of pathology; and Carl Morrison, assistant professor of pathology and of internal medicine.

Funding from the National Institute of Environmental Health Sciences and the National Cancer Institute supported this research.