By blocking a widespread enzyme, Centenary Institute amd Sydney Medical School researchers have shown they can slow down the movement of cells and potentially stop tumours from spreading and growing. Using a new super-resolution microscope the team were able to observe single molecules of the enzyme at work in a liver cancer cell line. The team also used confocal microscopes to see how disrupting the enzyme slows down living cancer cells. The enzyme is DPP9 (dipeptidyl peptidase 9) which the researchers were first to discover and clone in 1999.
The team viewed the enzyme at work and then block DPP9, and actually witnessed the cells slow down. The researchers state that the current study gives the clearest evidence yet that this enzyme is a viable cancer drug target. The work has shown is that this enzyme is absolutely critical to cell movement, and without cell movement, tumours can’t grow or spread.
Using a super-resolution microscope the team determined where individual fluorescently tagged DPP9 molecules were located inside cells. They found that DPP9 lies on the microtubules that play a significant role in intracellular transport and in cell migration.
When cells were stimulated to move, the team discovered DPP9 accumulates at the leading edge of the moving cell. DPP9 was also associated with the adhesion protein complex that glues the cell to the external matrix though which it moves, acting as an anchor point to pull the cell along. When the action of DPP9 was inhibited in cells, such movement and adhesion diminished.
Although DPP9 is looking more and more like a cancer drug target, at present there are no specific inhibitors for it, even though the medical community have been trying for some years to make one. The team state that more research is needed in this area.
During the past 15 years the team have been unveiling the properties of DPP9, which belongs to a small family of four enzymes specialised in cleaving other proteins. Members of this family modify and regulate proteins for many important functions inside and outside of cells. DPP4, for instance, is already the basis of a leading drug treatment for diabetes. DPP4 inhibitors are worth about $6 billion a year and comprise about a quarter of the diabetes drug market.
The roadblock to developing a specific inhibitor for DPP9 has been that it is very similar physically, but not functionally, to DPP8. It has been hard to distinguish between the two chemically. The team is now working on determining and publishing differences between the two enzymes, which should help the medical community target their efforts better.