Switching off enzymes to block cell division in cancer

Cell division
Cancer is characterized by the uncontrolled proliferation of cells. Targeting cell division is an attractive approach to slowing or preventing cancer growth. (University of Chicago)

Researchers from Sweden and the U.K. have devised a new method to curb cancer growth by shutting down a single enzyme and stopping cells from dividing.

While switching off certain enzymes is an attractive approach to treat cancer, it can be difficult to create a drug that targets just one enzyme out of the thousands in the human body, the researchers from Uppsala University, Karolinska Institutet, and the University of Oxford said in a statement.

The team zeroed in on the enzyme dihydroorotate dehydrogenase (DHODH), a membrane protein and a new cancer target. They used a method called nondenaturing mass spectrometry, alongside molecular dynamics simulations, to study how lipids and inhibitors bind to DHODH.

"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 Institutet. DHODH also binds a lipid in the cell’s mitochondrial respiratory chain complex, suggesting the enzyme might use special lipids to locate the correct binding site on the cell membrane, Landreh said.

"Our simulations show that the enzyme uses a few lipids as anchors in the membrane,” said Erik Marklund of Uppsala University. “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.”

Attacking cell division to slow cancer growth is a popular idea, for the simple reason that the abnormal growth of cells is the very definition of cancer. Scientists at the Oxford Institute for Radiation Oncology and Cancer Research UK created radiation-carrying gold nanoparticles that target cell division by entering cells and shutting down telomerase. Found at the ends of chromosomes, telomerase allows cells to divide but degrades over time. In cancer, this breakdown is sabotaged, allowing the cells to multiply freely.

The gene-editing method CRISPR may also prove useful in keeping cancer growth in check. A University of Rochester team used CRISPR to remove Tudor-SN, a protein that plays a role in a preparatory phase of cell division. Cells without the protein took much longer to prepare for division, suggesting that the approach could be used to inhibit fast-growing cancer cells.

The new findings from the researchers in Sweden and the U.K. were published in Cell Chemical Biology. The scientists believe their insights could lead to the development of new, more selective cancer drugs.