Novel Cancer Treatment Method Blocks Enzyme That Plays A Role In Cancer Progression

Proteins
Scientists have discovered a molecule that can block the diseases causing NMT— enzyme’s action on proteins. Photo courtesy of Shutterstock

Cancer researchers have recently discovered the mode of action by which an enzyme promotes progression of cancers, and also ways to stop it. Developing therapeutics based on this research could save thousands who get afflicted by several types of this disease, known to be the leading cause of death in the United States. The research appears in the journal Nature Communications.

The disease-causing enzyme called N-myristoyltransferase (NMT) makes changes to proteins and thereby causes several diseases, including inflammatory conditions, cancers, and Alzheimer’s. The changes it causes to the proteins is known as myristoylation. This process plays an important role in several signal transduction pathways and involves irreversible modification of proteins in the cytoplasm of many organisms, including animals, fungi, protozoans, and viruses.

Increased myristoylation of proteins leads to enhanced cell proliferation and can be responsible for transforming normal cells into cancer cells. In the new research, scientists for the first time identified more than 100 proteins that NMT modifies, in living human cancer cells. And all of these proteins were identified in their natural environment.

The scientists mapped all of the proteins affected by NMT. They also found a small drug-like molecule that can block the activity of NMT and inhibit its ability to modify each of these proteins, suggesting a potential new way to treat cancer.

"We now have a much fuller picture of how NMT operates, and more importantly how it can be inhibited, than ever before. This is the first time that we have been able to look in molecular detail at how this potential drug target works within an entire living cancer cell, so this is a really exciting step forward for us,” said lead researcher Professor Ed Tate, from the Department of Chemistry at Imperial College London, in a statement.

"This 'global map' allows us to understand what the effects of inhibiting NMT will be. This means we can determine which diseases it might be possible to combat by targeting NMT, enabling us as a next step to explore how effective such treatments could be," Tate added.

In order to identify the proteins that get modified by NMT, the scientists conducted a large scale study using sophisticated and painstaking methods for several years.

They then developed a molecule and conducted mass spectrometry to observe its NMT inhibiting properties. For this, they induced a process called apoptosis, defined as programmed cell death, which occurs when the cell is under stress, such as DNA damage or lack of oxygen. This process is essential in cancer chemotherapy and is very often deactivated in drug resistant cancers. Although NMT has been known to cause apoptosis by affecting a few proteins, in this study the researchers identified many new proteins affected by NMT, suggesting new ways to combat drug resistance.

"On the back of these results we are looking to test a drug that will have the most potent impact on blocking NMT's ability to modify proteins, and we have started working with collaborators at the Institute of Cancer Research and elsewhere on some very promising therapeutic areas," Tate said, explaining the next stage in their research. "We are still at an early stage in our research but we have already identified several very potent drug-like NMT inhibitors that are active in animal disease models, and we hope to move towards clinical trials over the next five to 10 years." 

Source: Thinon, E. Tate E, et al. Global profiling of co- and post-translationally N-myristoylated proteomes in human cells. Nature Communications. 2014.

 

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