Curbing Cancer Growth

Cell Division Stops Cancer at its Source

Since cancer is defined as fast and unregulated cell growth, stopping it by destroying an enzyme that supports cell division represents an exciting new approach to fighting cancer, reports Amirah Al Idrus in Fierce Biotech.

It is difficult enough to target a particular enzyme out of the great number of them that are present in the body, but “membrane proteins” that are only active in the lipid environment in the cell membrane are even more elusive. Shutting down one specific enzyme out of thousands in the body is extremely challenging, several groups of researchers agree.

As reported in the journal Cell Chemical Biology, researchers at Uppsala University, Karolinska Institute and Oxford University are trying to discover exactly how anti-cancer drugs interact with enzymes at the cellular level. Scientists at Uppsala and Karolinska are studying the enzyme dihydroorotate dehydrogenase (DHODH) using nondenaturing mass spectroscopy, a process in which the sample protein is placed in a vacuum chamber and the time elapsed for the molecule to transmit the chamber is measured.

This gives researchers the molecule’s weight, in this case the DHODH, and that in turn allows them to see how both lipids and drugs are able to bind to the enzyme. "To our surprise, we saw that one drug seemed to bind better to the enzyme when lipid-like molecules were present," said assistant professor Michael Landreh of Karolinska Institute. Since it was also found that DHODH binds with a specific mitochondrial lipid, this means the enzyme might use special lipids to find its correct place on the membrane.”

The Uppsala team uses computer simulation to study DHODH. As lead researcher Erik Marklund explains, "Our simulations show that the enzyme uses a few lipids as anchors in the membrane. When binding to these lipids, a small part of the enzyme folds into an adapter that allows the enzyme to lift its natural substrate out of the membrane. It seems that the drug, since it binds in the same place, takes advantage of the same mechanism.”

“This study helps to explain why some drugs bind differently to isolated proteins and proteins inside while cells. By studying native structures and mechanisms for cancer targets, it may be possible to exploit their features to design new, more selective therapeutics,” adds Sir David Lane of Karolinska.

Another approach to stopping cell division is being explored at the Oxford Institute for Radioactive Oncology and Cancer Research. Here, tiny radioactive particles of gold are being introduced into cells to attack the enzyme telomerase, which facilitates cell division but then normally breaks down. This breakdown fails to happen in cancer.

Finally, the University of Rochester is using the gene manipulation technique CRISPR to remove a protein called Tudor-SN, which is also involved in cell division. Its loss causes a significant slowdown in cell replication.