Do cancer cells highjack an immune component to fuel tumor growth?
06 May 20
USC researcher Pinghui Feng investigates a potential way to stop cancer cell growth.
FOR CELLS IN THE BODY, inflammation and cell proliferation — a rapid increase in numbers — are opposing forces. Cells that proliferate more quickly tend to have a lower inflammatory response than those that don’t. The reason behind this has been investigated for many decades.
A new study, published in Cell Metabolism, details the intricate interplay between an enzyme called CAD and inflammatory pathways. The researchers found that cancer cells highjack this enzyme’s actions to grow faster — which could lead to new tools to fight cancer.
Inflammation typically sends up a flare, signaling a person’s immune system to attack a growing tumor. Tumors, on the other hand, try to hide from the immune system to save themselves and grow bigger.
Typically, cancer cells trigger inflammation that is mediated by the activation of immune pathways converging at a protein complex called NF-kB. This complex plays a key role in regulating the immune response to infection, and incorrect regulation of NF-kB has been linked to cancer, inflammatory and autoimmune diseases.
In this study, titled “Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis,” Ostrow Professor Pinghui Feng and colleagues from USC and China studied the CAD enzyme, which catalyzes nucleotide synthesis, the material essential for a cell’s genetic makeup.
“So there’s a potential link between metabolism, and then the regulation of NF-kB, which was not understood before,” Feng said.
While CAD is known to participate in the synthesis of nucleotides that are small molecules, the Feng group showed it also works on proteins, such as the NF-kB subunit.
Specifically, CAD removes ammonium from the side chain of two asparagines, one of the 20 amino acids that make up a protein. This process is known as deamidation, the simplest modification of protein known thus far. When deamidated, NF-kB no longer activates inflammatory response, instead installing a particular metabolic program to fuel cell proliferation.
This discovery could allow clinicians to do a thorough analysis of patient samples — for example, a colorectal tumor biopsy. Some patients with cancer may have mutations that create changes in the NF-kB complex.
“Using this information can help us stratify the cancer to guide us to treat this cancer, targeting this pathway to treat patients,” Feng said.
The discovery could also give scientists the ability to specifically block the CAD enzyme because cancer uses this system to avoid immune detection, all while promoting cell proliferation. So an inhibitor to the enzyme would block tumor creation — something that Feng’s lab is trying to develop now. The next most important thing to do is to find a way to get an inhibitor targeting tumor cells, Feng said. “And if so, can we use it to treat cancers?”
He added that scientists have traditionally questioned the role of protein deamidation – the way that the CAD enzyme affects the NF-kB complex — but he hopes there will be more people investigating this underexamined area of biology.
“I hope there would be more people working on this topic in the future,” Feng said. “This is really a neglected process, but it is also fundamental and important.”
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