| PROTEOLYSIS
INDUCING FACTOR AS A SURVIVAL AND PROLIFERATION FACTOR
IN PROSTATIC CARCINOMA CELLS AND ITS POTENTIAL AS A FUTURE
THERAPEUTIC TARGET.
Grant Stewart Mr Antony Riddick, Mr S Alan McNeill, Professor Kenneth C H Fearon, Dr Fouad K Habib and Dr James A Ross The Prostate Research Group, University of Edinburgh |
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Since taking up this grant from the Agnes Hunter Trust progress on the above project has been excellent.
The cancer cells composing a prostate cancer are often found under low oxygen conditions; this is because the rapidly growing cancer cells outgrow their blood supply so rapidly. Rather that causing the cancer cells to perish, the low oxygen levels (hypoxia) causes prostate cancer cells to produce a range of molecules which allow the cells to survive i.e. by producing new blood vessels, enhancing glucose delivery.
Previously research has demonstrated that prostate cancer cells can produce a molecule known as proteolysis-inducing factor (PIF). PIF is known to be responsible for weight loss in patients with advanced cancers. However, it has been established that the gene from which PIF is derived is a cancer causing gene in advanced breast cancer cells. Additionally, PIF appears to allow the survival of breast cancer cells as well as nerve cells when they are subjected to free radicals that exist in our daily environments. We have been investigating PIF in our laboratory for a number of years.
Our study aimed to establish: (i) does PIF allow the survival of prostate cancer cells found under hypoxia or oxidative stress, as they would be in a human prostate cancer?; (ii) what factors allow the upregulation of PIF production? A range of cell and molecular biology techniques have been used to answer these questions.
Firstly I identified a prostate cancer cell line that could be grown repeatedly in the laboratory, which did not produce the PIF molecule. I forced this cell line to produce PIF, using a technique called cell transfection. Transfecting the cells with PIF allowed me to examine what effect PIF has on growth and survival of prostate cancer. I determined that PIF allowed prostate cancer cells to grow more rapidly than those cells not producing PIF (figure 1). This result demonstrated that PIF may be important in the rate of prostate cancer cell growth.
 Figure 1. A growth curve showing the more rapid rate of growth of PIF expressing prostate cancer cells compared with cells unable to produce PIF. |
I then moved on to assess how PIF affected cells that were ‘stressed’ by hypoxia or oxidative stress, as they would be in a human tumour. I found that the ability of prostate cancer cells to express PIF protected them from cell death caused by such forms of cell stress. This survival benefit was in the region of 42% over cells unable to produce PIF (figure 2). These results suggest that PIF expression by prostate cancer may allow the survival of prostate cancer cells in the harsh tumour environment and allow the tumour to grow and progress.
 Figure 2. A graph showing a 42% survival advantage to prostate cancer cells able to express PIF after exposure to oxidative stress. |
Finally, I determined using a technique called real-time polymerase chain reaction that the production of PIF by prostate cancer cells was increased by exposure to both hypoxia and oxidative stress. This result illustrated to us that cancer cells not only have a growth and survival advantage if able to produce PIF but they also appear to increase the production of this protein by the very conditions they are attempting to evade.
Conclusions
From the results obtained thanks to the generous funding provided by
the Agnes Hunter Trust we believe that PIF is a potential target
for the treatment of prostate cancer. There is still a considerable
amount of work to be done to confirm that PIF is indeed worth considering
as a good target for the treatment of prostate cancer. I am continuing
this work which is making up my PhD thesis, with funding from Prostate
Cancer Research Campaign UK. I would like to thank the Agnes Hunter
Trust for their wonderful support of this research.
Presentations resulting from this grant:
- Proteolysis-inducing factor core peptide is a survival factor in prostate cancer cells subjected to hypoxia and oxidative stress. Poster presentation at the American Association of Cancer Research Annual Meeting, Los Angeles, USA, April 2007.
- Proteolysis-inducing factor core peptide: a novel survival factor in prostate cancer. Poster presentation at the British Prostate Group Spring Meeting, Newcastle, March 2007.
- Dermcidin: a novel survival and proliferative factor in prostate cancer. Oral presentation at Royal College of Surgeons of Edinburgh/College of Surgeons of Hong Kong Conjoint Scientific Congress, Hong Kong, October 2006.
Publications resulting from this grant:
- G.D. Stewart, A.G. Lowrie, A.C.P. Riddick, K.C.H. Fearon, F.K. Habib, J.A. Ross. Dermcidin expression confers a survival advantage in prostate cancer cells subjected to oxidative stress or hypoxia. The Prostate. Submitted.
- B. Wieland, G.D. Stewart, R.J.E. Skipworth, K. Sangster, K.C.H. Fearon, J.A. Ross, T.J. Reiman, J. Easaw, M. Mourtzakis, V. Kumar, B.J. Pak, K. Calder, G. Filippatos, D.T. Kremastinos, M. Palcic, V.E. Baracos. Is there a human homolog to the murine proteolysis–inducing factor? Clinical Cancer Research. Submitted.
- G.D. Stewart, A.C.P. Riddick, F.K. Habib, K.C.H. Fearon, J.A. Ross. Dermcidin: a novel survival and proliferative factor in prostate cancer. Surgical Practice 2006; 10 (Supplement): A17.
Summary of original research proposal dated 25 April 2007
Project 2006/02 which is a supplementary award to project 2005/04