May 10 2005
Researchers at the University of Dundee have identified a way of inactivating a naturally occurring human protein, a development which could offer new routes to developing cancer prevention treatments.
Professor John Hayes and Dr Lesley McLellan in the Biomedical Research Centre at the University, along with Dr Chris Lindsay, have found that the protein, called Keap1, is a target for a new class of cancer prevention treatments.
The researchers say the findings simplify the actions that could be taken to protect cells against cancer-causing chemicals.
"From a scientific point of view this is rather unexpected because previous papers have suggested that inactivation of Keap1 is not sufficient to switch-on anti-cancer defences but that other changes in the cell are also required. Importantly, we have found it is simpler than that. You only have to inactivate Keap1. Just a single target!" said Prof Hayes.
"This could be very important in future development of prophylactic treatments, and also in understanding what can happen in human cells as opposed to animal cells. Humans are not big mice, so to find the cleanest and simplest way of activating this defence system in humans, without causing side-effects, is extremely important."
More than 80% of cancer cases are attributable to environmental factors, and evidence suggests that many forms of malignant disease are avoidable. Well known risks include exposure to sunlight, cigarette smoke, asbestos, alcohol and some mould toxins.
Cancer susceptibility is influenced significantly by diet. We can help protect ourselves against cancer by eating diets that can stimulate natural defences of the cell against harmful chemicals. A large number of compounds found in plants, as well as synthetic food additives, have been shown to possess this ability. Broccoli, Brussels Sprouts, cauliflower, garlic and onion contain some of the compounds that can help prevent cancer. These dietary agents activate protective systems by causing small alterations in the normal antioxidant balance of the cell; this triggers cellular factors to increase levels of antioxidant and detoxification proteins as a compensatory mechanism.
In the past 5 years, experiments in model systems have shown that a protein called Nrf2 is responsible for controlling about 200 genes that are involved in a variety of protective processes in the cell. These Nrf2-regulated genes can provide defence against a spectrum of cancer-causing chemicals. Under normal conditions the Nrf2 protein is very unstable, and each molecule only survives for a few minutes in the cell. The instability of Nrf2 is due to its interaction with another protein called Keap1 that continually directs its destruction.
However, when the antioxidant capacity of the cell is depleted the stability of Nrf2 is increased at least 6-fold. This occurs because Keap1 somehow loses its ability to have Nrf2 targeted for degradation, but the details of this process are currently unclear. The antioxidant-dependent regulation of Nrf2 is a type of negative feedback control that acts to ensure protective genes are maximally switched on when the antioxidant balance of the cell is disturbed. It represents a form of adaptation of the cell to its environment.
As described in a paper published on May 9 in the Proceedings of the National Academy of Sciences USA, the laboratories of Prof Hayes, Dr McLellan and Dr Lindsay have designed a nucleic acid molecule, of the type called siRNA, which interferes with the expression of Keap1.
When introduced into human skin cells, they found that the siRNA against Keap1 caused levels of Keap1 to become depleted, resulting in accumulation of Nrf2 and activation of antioxidant genes.
"This is an important finding because it means that cellular defences can be increased without a need for their antioxidant status to be first compromised, an event that on occasions could lead to lasting damage," said Prof Hayes.
"It means that cells can be pre-prepared for exposure to noxious chemicals. From a scientific point of view, these findings show that inhibition of the function of Keap1 is sufficient to activate protective genes; it is not essential that Nrf2 is activated by chemicals that deplete antioxidant levels before defence genes are induced.
"It should now be possible to define for the first time the human genes that are regulated by the Nrf2/Keap1 pathway. This is important to our understanding of cancer chemoprevention in humans because it is already clear that the Nrf2-dependent response in humans is different to that found in other organisms.
"Furthermore, this study will facilitate identification of the kinds of cancer-causing chemicals that human cells can be protected against by the Nrf2/Keap1-dependent adaptive response. In summary, the findings of the paper suggest that inhibition of Keap1 activity is sufficient to enhance the antioxidant capacity of human cells and that this could help protect against the development of cancer."