Turning off Tumors
Turning off Tumors
A team of Penn State scientists has devised a new strategy for “reactivating” genes that cause cancer tumors to shrink and die, and tested it in mice with promising results. The researchers hope their discovery will one day aid in the development of an anti-cancer drug that effectively and selectively targets cancerous tissue.
Led by Yanming Wang, associate professor of biochemistry and molecular biology, and Gong Chen, assistant professor of chemistry, the team has focused its efforts on a gene called PAD4 (peptidylarginine deiminase 4), which produces the PAD4 enzyme.
Previous research by Wang and others had revealed that the PAD4 enzyme plays an important role in protecting the body from infection. In experiments with mice, the researchers discovered that cells with a functioning PAD4 enzyme, unlike those in which the enzyme is defective, are able to build around themselves a protective, bacteria-killing web that Wang and his colleagues dubbed a NET (neutrophil extracellular trap).
Ironically, over-expression of the same PAD4 gene may be linked to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In patients with certain cancers, such as breast, lung, and bone cancers, Wang adds, production of PAD4 enzyme is markedly increased.
As he explains it, the PAD4 gene’s apparent dual personality is a byproduct of evolution—and the lengthening of the human lifespan. “Our ancestors didn't have antibiotics, so a bacterial infection could easily result in death, especially in young children,“ Wang says.
“Back then, an overactive PAD4 gene was advantageous because the NET bacteria-trapping mechanism was the body's major defense against infection,” he adds. With today's access to antibiotics, however, people live much longer than their ancestors did. “PAD4’s bad effects—cancer and autoimmune diseases—tend to be illnesses that appear later in life,” Wang says. “So nowadays, an overactive PAD4 gene, while still protective against bacteria, can be detrimental later in life."
In the case of the current research, “We know that the PAD4 gene acts to silence tumor-suppressor genes,” Wang continues. “So we theorized that by inhibiting the enzyme that this gene produces, the ‘good guys’—the tumor-suppressor genes—would do a better job at destroying cancerous tissue and allowing the body to heal.”
To test their theory, he and his colleagues treated mice that had cancerous tumors with a molecule to inhibit the PAD4 enzyme. They found that, especially when combined with additional enzyme inhibitors, the treatment worked as effectively as the most-commonly-used chemotherapy drug, doxorubicin, which shrinks tumors by about 70 percent.
More striking, however, was that the PAD4 enzyme-inhibition strategy caused significantly less damage to healthy tissue. “Current chemotherapy drugs such as doxorubicin don't attack just tumors; unfortunately, they also attack healthy areas of the body,” Wang explains. “That's why chemotherapy patients experience such terrible side effects. Because the PAD4 treatment appears to be less toxic, it could be an excellent alternative to current chemotherapy treatments.”
Their research was funded by the National Cancer Institute and a Penn State Clinical and Translational Science Institute Pilot Grant Award. The results reported above will be published in the Journal of Biological Chemistry.