Scientists at the Johns Hopkins Kimmel Cancer Center have discovered that an enzyme found in a tumor cell's energy center has a special relationship with a gene that controls cancer cell growth and death. Their findings, published in the May 14 issue of the Proceedings of the National Academy of Sciences, may offer a road map to anti-cancer therapies designed to manipulate the genetic pathway that switches the enzyme on and off.
The enzyme PRDX3 inhabits mitochondria, the tiny organelles that provide energy to cells and a meeting ground for regulation of cell life and death. "What this research suggests is that we might be able to shut down tumors by learning how to control this enzyme," says Chi Dang, M.D., Ph.D., director of the division of hematology and professor of medicine, cell biology, pathology and oncology.
Proteins made by the PRDX3 gene, known to be overexpressed in breast cancer, chew up or reduce oxidants, called peroxides entering the cell. Hopkins investigators used a scanning method to "skip" through pieces of the PRDX3 gene and precisely pinpoint areas where certain proteins bind to it, acting like ignition switches to increase expression. The investigators found that a key ignition switch controlling activation of PRDX3 is a well-known cell growth-promoting cancer gene called c-MYC.
To find out how c-MYC and PRDX3 work together, the scientists looked at different levels of PRDX3 activation in rat and human cancer cell lines where c-MYC was turned on. When they shut down PRDX3, turning off its ability to make its enzyme, the mouse tumors stopped growing. When they turned it back on, tumors grew rapidly.
"Think of PRDX3 as a light bulb and c-myc as the light switch. If you remove the light bulb even though the switch may be on, the lamp still doesn't work," explains Dr. Dang. "In this case, we've removed the light bulb rendering the switch powerless."
"These results show that changing PRDX3 activation can alter how tumors grow. Now, our challenge is to find out in which cancers this pathway is most important and what drugs may do the job," says Dr. Dang.
This research was funded by the National Cancer Institute, National Institutes of Health.
Other participants in this research were Diane Wonsey and Karen Zeller of Johns Hopkins.
Reference: Diane R. Wonsey, Karen I. Zeller, and Chi V. Dang, "The c-MYC target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation," Proceedings of the National Academy of Sciences, May 2002, Vol. 99, Issue 10: pp. 6649-6654.
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