Funded Research 2004

Nitric oxide - voltage-gated Na + channel interaction in prostate cancer metastasis
Prof M B A Djamgoz PhD ARCS DIC FSMC FIBiol, Department of Biological Sciences, Imperial College London

The statistics concerning PCa are now well known. Whilst the scale of the problem continues to grow in the western world, there has not been a significant conceptual advance in the therapy of PCa since the classic work of Huggins, concluded in the 1940's, showing the effectiveness of androgen ablation (surgical or hormonal castration). Unfortunately, however, this is effective only for a limited period (2-5 years) and then the cancer spreads especially to bones and can lead to painful death. The early diagnosis of PCa, which could enable lasting treatment, also continues to be a problem due to the uncertainty of the commonly used prostate specific antigen (PSA) method.

In a novel approach to understating PCa, especially its spread (“metastasis”), we have used for the first time the powerful “patch-clamp” recording technique and discovered that human PCa cells destined to spread express a particular “voltage-gated sodium channel” (VGSC). This is a functional protein which is expressed early and enhances metastatic behaviour by potentiating PCa cells' motility, secretion and invasiveness. In essence, therefore, detection of VGSC espression can enable distinction of slow-growing, clinically insignificant tumours from those that are aggressive, will metastasise and hence must be removed as soon as possible whilst the tumour is still confined to the gland. Furthermore, blocking VGSC activity suppresses metastatic behaviour so the protein is also of therapeutic potential.

Indeed, a recent report from USA (following our work) has suggested that VGSC blockers are “cytostatic inhibitors” of andreogen-independent prostate cancer [Anderson et al. – Molec Cancer Therapeut].

A major question in this work is what regulates VGSC expression and activity. We have found recently that VGSC activity enhances nitric oxide (NO) release from metastatic rat PCa cells. This work has led to the hyposthesis that there could be a positive feedback loop between VGSC activity and NO production which can contribute to progression of PCa. However, many details of the two main mechanisms and their interaction are not known. Both NO and VGSC have been associated with progression of cancer, including PCa and it is readily possible that these two mechanisms are strongly interactive. For example, NO is known to enhance VGSC activity.

This project will investigate this hypothesis using first the Dunning model system of rat PCa, which comprises a range of cell lines with distinct metastatic phenotype and electrophysiological character, and thus offers major experimental advantages. Analogous human PCa cell lines will also be tested. A multifaceted approach will be used, with the following lines of investigation being pursued:

• Basic characteristics NO synthesis and release
• Testing of a possible reciprocal NO – VGSC interaction
• Functional aspects of NO on metastatic cell behaviours
• Studies carried out in vivo and establishment of clinical relevance
  
  
  Project commenced
  July 2004
  
  Length of project
  1 year
  
  Amount Supported
  £7,500
  
  

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