Tuesday February 1 2011
Boosting the FUS protein reduced tumours in mice
“Prostate cancer ‘can be made to kill itself’ by newly found protein,” according to the Daily Mail. The newspaper said that “a drug that boosts levels of the protein called FUS could stop the disease from spreading around the body”.
The news is based on laboratory research that used a number of experiments to investigate the role of the FUS protein in prostate cancer cells. Notably, when researchers injected laboratory mice with prostate cancer cells and genetically boosted the mice's FUS production, they saw decreases in the size of the tumours they had developed. Greater levels of the FUS protein in human prostate tumour samples were also associated with cancers that were less advanced.
This was useful research that warrants further study. Further research will now be needed to gauge the role of FUS in non-cancerous cells in the body and to determine whether the protein will be a viable candidate for future drugs to target.
Where did the story come from?
The study was carried out by researchers from Imperial College London and was funded by Prostate Action, the Medical Research Council, The Prostate Cancer Charity and Imperial College. It was published in the peer-reviewed medical journal Cancer Research.
This research was covered accurately, in general. The Daily Telegraph highlighted the preliminary nature of this research well.
What kind of research was this?
This was laboratory research that investigated proteins that may play a role in prostate cancer. Prostate cancer responds to male hormones (androgens), which encourage prostate cancer tumour growth. Some treatments for prostate cancer involve stopping androgen production or blocking receptors that are activated by androgens. However, although this strategy may initially be successful, prostate cancer can progress to a more aggressive “hormone-nonresponsive” state, for which few drug options exist.
The researchers wanted to see whether they could find proteins that were regulated (in other words, their production in the cell increased or decreased) in the presence of androgens. They were particularly interested in a protein called FUS (Fused in Ewing’s Sarcoma). This protein is thought to be involved in regulating several steps in the production of other proteins.
What did the research involve?
The researchers exposed cells in culture to synthetic androgens, isolated the proteins they contained and identified proteins that had either increased or decreased in the presence of androgens.
The researchers wanted to see what the role of FUS was in cells, so they then performed a number of tests using cell lines, which are extracted cells grown in self-sustaining cultures. The researchers first genetically modified a cell line so that it would produce more FUS than a normal cell. They used a cell line called LNCaP that was derived from a human prostate tumour. These cells are sensitive to androgen and have a receptor that binds to androgens on their surface. The researchers also used a technique called siRNA to reduce the amount of FUS in these cells.
After investigating the effects of increased FUS in cells in culture, the researchers looked at the effect of this protein in mice. They injected mice with the same LNCap human prostate cancer cell line that they had used for the cell culture experiments. They were then able to switch on the over-production of FUS by giving the mice a chemical called doxycycline. They also stimulated the tumours to grow by giving the mice testosterone, before switching on the production of FUS by giving the mice doxycyline.
Finally the researchers looked at FUS levels in tumour biopsies from men who had prostate cancer and looked at whether there was any association between the level of FUS and the severity of the cancer and the prognosis for the patient.
What were the basic results?
The researchers found that there were lower levels of the FUS protein in cells that had been exposed to androgen. When cells were exposed to androgen for 72 hours, there was 90% less FUS in them.
When more FUS was produced by the LNCaP cancer cells they stopped growing (dividing). When the researchers lowered the FUS levels in the cells, the growth rate of these cells increased.
To understand why increasing the FUS protein stopped cells from growing, the researchers looked at whether there were differences in the amounts of other proteins in the genetically modified cells producing more FUS protein. They found that the amount of the proteins cyclin D1 and CDK6 were decreased and the levels of kinase inhibitor p27 was increased. The Cyclin D1 and CDK6 proteins are involved in cell division.
The researchers also found that increasing FUS in the cells caused a type of programmed cell death, called apoptosis. In mice where FUS over-production had been switched on, there was a decrease in tumour size over seven days.
Analysing tissue samples of prostate tumours taken from 114 men with prostate cancer showed that those whose prostate biopsy sample contained high levels of FUS were less likely to have more advanced or aggressive cancer. They were also less likely to have had their prostate cancer spread to the bones. Men producing high levels of FUS were more likely to have a longer survival, living a further 91.8 months on average. Men expressing low levels lived for 70.8 months on average.
How did the researchers interpret the results?
The researchers said that their findings suggest that FUS regulates factors that are important in the cell cycle progression and that androgens lower FUS. The finding that FUS expression is reduced in the late stages of cancer may enhance androgen signalling and promote cancer cell growth. They say that as they demonstrated that increasing FUS levels in animal models reduces tumour growth, methods to manipulate FUS levels could be useful in the treatment of prostate cancer.
This was well-conducted preliminary research that demonstrates the role of the FUS protein in the androgen response of prostate cancer cells in the laboratory, and in animal models. It also shows that FUS levels are inversely associated with tumour grade in human biopsy samples; in other words, that higher FUS levels were associated with less advanced cancer.
In an animal model of prostate tumours (where tumours were induced by injections of cancer cells), the researchers showed that it was possible to shrink the tumours by modifying cells to produce greater amounts of the FUS protein. Further research is needed to see the effect of FUS in other non-cancer cells in the body, to see whether using this protein as a drug target in cancer is a feasible approach.
As it stands, this research has contributed to the understanding of how prostate tumour cells divide and how male hormones such as testosterone may affect this.