| ANDROGEN
REGULATION OF VOLTAGE-GATED SODIUM CHANNEL EXPRESSION:
A NOVEL METHOD IN METASTATIC PROSTATE CANCER.
Professor Mustafa Djamgoz Imperial College London, Division of Cell & Molecular Biology |
 |
The prostate gland is a part of the male reproductive system. It produces about one-third of the ejaculate and provides nourishment to sperm. Prostate is very sensitive to the male hormone testosterone (an androgen) which normally maintains a healthy balance between cell division and cell death. During the aging process, however, the balance in the action of testosterone on prostate changes in favour of increased proliferation and gradually local tumours form. This is the beginning of prostate cancer (CaP). Thus, about 50% of men at the age of 50 have CaP and this rises to 80% by the age of 80. As long as the tumours remain confined to the gland, they pose no real danger to men's health and men were said to "die with CaP". However, with time, tumour cells can escape from the prostate, enter blood circulation and spread to other organs where they attach, re-grow and form secondary tumours, a process called "metastasis" which is the main cause of death in most CaP patients.
With ever increasing life expectancy, there is more and more chance that CaP spreads and consequently more and more men are now "dying of CaP", presently at a rate of one man every 2.5 minutes! Fortunately, by stopping the action of androgen (by castration or chemically using drugs), CaP can be controlled. Unfortunately, however, this treatment only works for about 2 years, whereupon the disease returns, often with a vengeance, and death will result within subsequent months. Since CaP frequently spreads to bones, death from CaP can be very painful.
Thus, androgen represents a mainstream mechanism in CaP and androgen ablation, which is a classic treatment method, works, albeit for limited time. In order to prolong the period of its effectiveness, we need to understand how androgen acts to control CaP and its spread. To this end, we adopted concepts and techniques from brain science ("neuroscience"), exploiting the immense knowledge that accumulated during the "decade of the brain" in the 1990s. In particular, using very fine probes we recorded the electrical signals in CaP cells capable of spreading and compared these with the signals of cells that cannot spread. Thus, we found that aggressive CaP cells only possess a protein called a "voltage-gated sodium channel" (VGSC), specifically its subtype Nav1.7. Ion channels generally occur in many different cell types and their expression going wrong (qualitatively or quantitatively) can cause diseases, such as cystic fibrosis, cardiac arrhythmia, diabetes etc. We are the first to study ion channel in cancer cells. In CaP cells, the sodium channel protein sits in the cells' membrane and if the voltage across the membrane changes (say, in response to an external stimulus, like a hormone) it opens and allows sodium to enter the cell. In turn, this sodium can affect the cells' acidity, enzyme activities and structural properties. The net result is that the cells become excited, hyperactive and invasive. By blocking the channels (using a highly specific natural toxin, tetrodotoxin, or drugs like local anaesthetics) we can suppress the CaP cells invasive behaviour and we have recently done this also in animals (Copenhagen rats). Thus, VGSC (Nav1.7) is a novel target of the action of androgen.
The proposed project combines these two major mechanisms in CaP: Androgen and VGSC (Nav1.7). Our preliminary evidence suggests that androgen suppresses Nav1.7 expression. So, as far as the role of the channel in the disease process is concerned, it may not be surprising that androgen ablation may be detrimental to the patient since it will ultimately have the effect of causing the channels' expression to be increased and that will promote invasive behaviour. Accordingly, our first proposed main task is to understand the functional relationship between androgen and the channel. Evidence has also been emerging from the field generally that androgen can act on receptors on the cell surface ("non-classic") as well as inside the cell, on the nucleus ("classic"). Our second proposed aim, therefore, is to elucidate this novel mode of action of androgen, again focusing upon VGSC (Nav1.7) expression.
The best and most precise way of reaching this in-depth understanding would be at a fundamental, molecular level. We recently identified the part of the gene that controls the channels' expression, so we are uniquely positioned with all the necessary tools to undertake the proposed studies.
Research summary, 04 March 2008.
Project 2007/08