New Approach Triggers Genes That Inhibit Tumor Activity

A team of scientists has developed a potential new application for “reactivating” genes that cause cancer tumors to shrink and die. The researchers hope that their discovery will aid in the development of an innovative anticancer drug that effectively targets unhealthy, cancerous tissue without damaging healthy, non-cancerous tissue and vital organs.

The research is planned for publication in the Journal of Biological Chemistry. The investigators, led by Dr. Yanming Wang, a Pennsylvania State University (Penn State; University Park, USA) associate professor of biochemistry and molecular biology, and Dr. Gong Chen, a Penn State assistant professor of chemistry, developed the new strategy after years of earlier research on a gene called PAD4 (peptidylarginine deiminase 4), which produces the PAD4 enzyme.

Earlier research by Dr. Wang and other scientists revealed that the PAD4 enzyme plays an important role in protecting the body from infection. The scientists compared normal mice with a functioning PAD4 gene to other mice that had a defective a PAD4 gene. When infected with bacteria, cells from the healthy mice attacked and killed approximately 30% of the harmful bacteria, while cells from the defective mice battled a mere 10%. The researchers discovered that cells with a functioning PAD4 enzyme are able to construct around themselves a protective, bacteria-killing grid that Dr. Wang and his colleagues called a NET (neutrophil extracellular trap). This NET is particularly effective at fighting off flesh-eating bacteria.

Now, in their new study, Dr. Wang and his collaborators have concentrated on the less-desirable effects of the same PAD4 gene. While PAD4 is clearly a critical part of the body’s defense strategy, the gene’s overexpression may be linked to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. One situation in which the PAD4 enzyme is markedly increased is in patients with certain cancers, such as breast, lung, and bone cancers. “We know that the PAD4 gene acts to silence tumor-suppressor genes,” said Dr. Wang. “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 evaluate their hypothesis, Dr. Wang and his colleagues treated mice that had cancerous tumors with a molecule to suppress the PAD4 enzyme. They discovered that, particularly when combined with additional enzyme inhibitors, the treatment worked as effectively as the most typically used chemotherapy drug, doxorubicin, which shrinks tumors by approximately 70%.

Most amazing, however, was that the PAD4 enzyme-inhibition approach caused considerably less damage to healthy tissues. “Current chemotherapy drugs such as doxorubicin don’t attack just tumors; unfortunately, they also attack healthy areas of the body,” Dr. Wang explained. “That’s why chemotherapy patients experience such terrible side effects such as weight loss, nausea, and hair loss. Because the PAD4 treatment appears to be less toxic, it could be an excellent alternative to current chemotherapy treatments.”

Dr. Wang also explained that the PAD4 gene’s dual character--on the one hand, a helpful defense against bacteria, while on the other, a harmful silencer of cancer-suppressor genes--can be understood from the standpoints of evolution and longer life spans. “Our ancestors didn’t have antibiotics, so a bacterial infection could easily result in death, especially in young children. So, back then, an overactive PAD4 gene was advantageous because the NET bacteria-trapping mechanism was the body’s major defense against infection.”

Dr. Wang also explained that, conversely, because people now have access to antibiotics, they live much longer than our ancestors did. “PAD4’s bad effects--cancer and autoimmune diseases--tend to be illnesses that appear later in life,” Dr. Wang said. “So nowadays, an overactive PAD4 gene, while still protective against bacteria, can be detrimental later in life.”

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