Researchers at the Sloan Kettering Institute have made some discoveries related to malfunctioning in and their progress points to a new approach to develop targeted drugs for cancer and other diseases, Alzheimer’s.
In Molecular Biology, it is known that if your chaperone proteins don’t fold the way that they are supposed to, it’ll result in the development of diseases which can be fatal to health.
“Our earlier work showed that defects in chaperones could lead to widespread changes in cells, but no one knew exactly how it happened. This paper finally gets into the nuts and bolts of that biochemical mechanism. I think it’s a pretty big leap forward.”
SKI scientist Gabriela Chiosis, senior author of a study published in Cell Reports.
The research focused on a chaperone called GRP94, which plays an important role in regulating how cells respond to stress. Stress in cells is a common sign of disease, especially those related to aging, such as cancer and Alzheimer’s. Dr. Chiosis has studied the role of chaperones and stress in both of these disorders for many years.
In the new study, Dr. Chiosis and her colleagues looked at changes in GRP94 in cancer cells. They found that when GRP94 undergoes a process called glycosylation, in which a sugar molecule is added, it completely changes the way that chaperone behaves.
“It goes from protein that was very floppy and flexible to one that’s very rigid,” explains Dr. Chiosis, a member of SKI’s Chemical Biology Program. “This one change is enough to convert it from a good guy in the cell to a bad guy. That, in turn, can make the cell behave in a way that’s not normal.”
SKI scientist Gabriela Chiosis, senior author of a study published in Cell Reports.
When GRP94 undergoes this change, it moves to a different part of the cell. Normally, it’s found in the endoplasmic reticulum, where proteins are made and folded. But after the sugar is added, it moves to the part of the cell called the plasma membrane. This leads to widespread dysfunction of proteins and a more aggressive cancer.
They have reported to have already identified a small molecule PU-WS13 called acts on GRP94 in the plasma membrane. It repairs the defects in GRP94 allowing it to behave normally again.
“The changes that we saw only happen in diseased cells, such as cancer cells or those related to Alzheimer’s,” said Dr. Chiosis. “That makes them a good target for therapies because healthy cells are unlikely to be affected.
She also added that the drug needs to be researched fully before developing it into a drug that would be tailored for human use.