Catenation, the intertwining of replicated DNA, is a delicate business. It helps bi-orient sister chromatid pairs during cell division, but it must be resolved before the chromatids are separated. Otherwise, DNA can be so ravaged during cell division that cell death ensues. This sort of cell death would seem to pose a special risk to cancer cells, which contains DNA that is more jumbled and prone to tangles. But cancer cells may resort to a slippery trick: the protein kinase C epsilon (PKCε) pathway. Denying cancer cells recourse to this pathway, which is seldom used by healthy cells, could offer a line of attack against cancer.
The suggestion that blocking the PKCε pathway could undermine cancer emerges from work completed by Cancer Research UK scientists. They assert that interfering with the machinery that untangles DNA could cause cancer cells to self-destruct.
The researchers presented their findings December 8 in Nature Communications, in an article entitled, “Mitotic catenation is monitored and resolved by a PKCε-regulated pathway.”
“We determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the [spindle assembly checkpoint] only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores.”
This pathway, the researchers continued, is necessary to facilitate resolution of retained catenanes in mitosis: “When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH [Plk-1 checkpoint helicase]-positive strands and chromosome bridging.”
Lead researcher Nicola Brownlow, Ph.D., Cancer Research UK scientist at the Cancer Research UK London Research Institute, said: “Taking out this line of defense could be a powerful way to target the disease and reprogram cancer cells to self-destruct.
“The next step in our research is to understand which cancer types have this weak spot and to look for a marker that will allow us to test patients for cancers with this fault.”
Nell Barrie, Cancer Research UK's senior science information manager, said: “This research has uncovered an important weakness which we could use to tackle cancer. Newer, precise methods which target the dents in cancer's armory provide fresh opportunities for better treatments to help more people survive the disease.”