New Yorkers are familiar with the sight (and smell) of uncollected garbage piled high along city streets. When inclement weather or holidays interrupt scheduled pickups, the fallout quickly mounts.
Cells have their own kind of garbage collector: an enzyme called DJ-1. This trusty sanitation worker collects harmful by-products of metabolism and disposes of them safely.
The garbage in this case is unstable chemicals that form when cells break down sugar. These chemicals react with vital proteins, cross-linking them and hobbling their function, a process is called glycation.
“Because of the way they consume nutrients, cancer cells produce a lot of metabolic waste products,” Dr. David says. “But we found that they also have more garbage collectors to haul this waste away.”
By increasing the activity of DJ-1, cancer cells avoid being poisoned by their own overzealous feasting, the team discovered. These findings suggest that DJ-1 could be a potential therapeutic target in cancer.
A Widespread Disease Hallmark
Dr. David first became interested in glycation because of its known links to diabetes and neurogenerative diseases such as Parkinson’s. Glycation is in fact the “the hallmark of diabetes,” she says. The diagnostic test for diabetes measures the level of glycated hemoglobin in the blood, called hemoglobin A1C.
In the case of neurodegeneration, brain cells are vulnerable to glycation damage because they live so long. The glycation damage builds up over time and can change the cells’ function and fate.
There’s even a link to aging itself. Skin wrinkles as it ages because the collagen proteins in skin become glycated and linked together, making them less flexible and supple.
The David lab found that the proteins most highly affected by glycation are histones — the spool-like proteins around which DNA is wound to form chromatin. Cells can chemically modify their histones to control which genes are turned on or off. Through these so-called epigenetic mechanisms, a cell’s behavior and identity, and thus its likelihood of becoming diseased, can be changed.
Cells have some natural defenses against glycation. These include the molecule carnosine, which scavenges the toxic by-products that trigger it. But when glucose levels are chronically high, as they are in diabetes, a cell’s defenses against these by-products can be overwhelmed. Glycated proteins begin to build up. This can have dangerous consequences for gene expression.Back to top
Linking Glycation to Cancer
Dr. David and Qingfei Zheng, a postdoctoral fellow in the David lab, suspected that histone glycation would be a particularly challenging problem for cancer cells. That is because cancer cells rely on a type of metabolism called aerobic glycolysis that is known to generate lots of unstable chemical by-products.
To test their hypothesis, they first wanted to show that the products of glycolysis would directly lead to glycation of histones. They put one such chemical, called methylglyoxal (MGO), in a test tube with cells and measured the resulting glycation. Indeed, MGO caused a spike in the glycation of histones but not other proteins. Using advanced biophysical methods (in collaboration with Shixin Liu from The Rockefeller University), they then found that these glycated histones caused the chromatin to become disrupted.
Next they wanted to know if histone glycation could be undone. The enzyme DJ-1 had previously been discovered to protect cells from stress, including the stress of glycation. Dr. David and her colleagues found — for the first time — that DJ-1 specifically removes the glycation from histones, preserving their function as caretakers of genetic information.
The proteins most highly affected by glycation are histones — the spool-like proteins around which DNA is wound to form chromatin.
To determine whether cancer cells are disproportionally affected by glycation, they worked with Sarat Chandarlapaty, a physician-scientist from the Human Oncology and Pathogenesis Program at MSK, to obtain samples of human breast cancer tissue. They found that these tumor samples had high levels of glycated histones as well as high levels of DJ-1 — 50 times the amount present in normal cells, explains Dr. Zheng.
Interestingly, when DJ-1 was removed from the cancer cells, they died. To the scientists, this result suggests that the cancer cells in these tumors were “addicted” to the cleanup action of DJ-1, which allows them to continue growing rapidly without suffering damage.
This gives the scientists an opportunity: targeting DJ-1 as a cancer treatment. They are currently working with the Tri-Institutional Therapeutics Discovery Institute and the Center for Experimental Therapeutics at MSK to develop small molecule drugs that can specifically interfere with the function of DJ-1 in cancer cells.
However, the therapeutic implications don’t end there. Some evidence suggests that diets high in alcohol and sugar can also tax the cell’s natural scavenger systems, leading to the formation of glycation products.
“Understanding the damage caused by glycation has far-reaching implications for the treatment of many diseases with known links to modern lifestyles,” Dr. David says.Back to top