Prostate cancer : the significance of the cAMP signalling pathway

• Main Author: Willis, Miranda Jane
• Published: University of Glasgow 2014
• Subjects: 616.99; QH345 Biochemistry
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616463

Prostate cancer is the leading form of male cancer in western countries. However, despite a great deal of interest from the scientific community, the cause still remains elusive. What is clear, is that androgenic signalling is important within prostate cancer progression, with early cancer under androgenic control and androgen regulated genes, such as PSA, commonly used for patient prognosis and progression. 3',5'- cyclic adenosine monophosphate (cAMP) is an important second messenger signalling molecule, which has been extensively studied within the field of oncogenesis. cAMP signalling effects are transduced via its effector molecules, PKA and EPAC, and the temporal and spatial control of cAMP dynamics are orchestrated by phosphodiesterase enzymes (PDEs). This signalling pathway has been implicated in a wide range of cellular processors such as, cellular differentiation, transcription, proliferation, apoptosis and learning and memory. In addition, it has also been linked to steroid receptor signalling such as oestrogen, progesterone, and androgen receptors. PKA can be expressed as 2 forms (PKA-I and PKA-II) depending on the regulatory unit isoform content of the enzyme. In the field of cancer research, PKA-I and PKA-II expression profiles have been shown to be linked to the phenotype of the cancer, i.e. overexpression of PKA-I is linked to a more proliferative cancer. Furthermore, other protein intermediates within the cAMP signalling pathway, including PKAC isoforms (PKA catalytic unit) and PDEs, change with respect to isoform expression and regulation during cancer progression. In this thesis, I have described my original research in which I endeavoured to understand the role of several components of the cAMP signalling axis in human prostate cancer. I have profiled the isoforms of PKA in androgen sensitive and insensitive prostate cancer, identifying isoforms that are dysregulated in the androgen independent disease stage. In particular, I found a down regulation of PKARIIβ and PKACβ isoforms in AI prostate cancer compared to AS. The function of these isoforms are not well categorised in prostate cancer. Due to the higher expression of these isoforms in AS cells, I went on to scrutinise these isoforms in relation to their interaction with androgenic signalling. Here, I have uncovered previously undiscovered aspects of PKA signalling, including the direct interaction of PKARIIβ and PKACβ isoforms with the androgen receptor (AR), and that PKA can phosphorylate the AR at site S791. Further analysis of this putative phosphorylation site would be beneficial to isolate a functional output. In addition, following previous work in the laboratory that identified PDE4D7 as a potential biomarker in prostate cancer, I have investigated novel-PDE4D7 controlled signalling pathways using cutting edge techniques. This data allows a better understanding of the mechanism behind the alteration of PDE4D7 driven signals and their significance during prostate cancer progression. Given more time and scrutiny, changes in these identified novel-PDE4D7 controlled signalling pathways, such as N-MYC, could show sites for exciting study into prostate cancer progression.