Investigating the mechanism of action and potential efficacy of Apolipoprotein E mimetics as therapeutic agents for the treatment of metastatic prostate cancer

Prostate cancer is the most prevalent non cutaneous cancer diagnosed in Irish men and the third leading cause of death in males annually in Ireland. Therapeutic strategies currently consist of prostatectomy or radiation followed by androgen ablative therapy. Typically, these treatment measures eventually fail. Prostate cancer re-occurs in the form of androgen independent prostate cancer, a lethal form of progressive and metastatic prostate cancer for which there is no cure. There is therefore an urgency for the development of more effective therapies. Apolipoprotein E (ApoE) has been reported in the literature to possess the ability to impede invasion and inhibit metastatic cell recruitment in cancer cells. ApoE has also been reported to have anti-inflammatory properties that could potentially impede pathogen recognition receptor (PRR) signalling. ONCOTIDE.inc generated a series of ApoE derived peptides modelled on the receptor binding domain of ApoE. The potential efficacy of the ApoE peptide mimetics COG112 and OP449 in prostate cancer were explored in this study. The aim of this study was to determine the toxicity of ApoE peptide mimetics to prostate cancer cells and the effect on cell cycle progression. The study also explored the ability of COG112 and OP449 to interact with the SET oncogene and modulate the SET-PP2A complex and PP2A activity. As chronic exposure to inflammatory stimuli is thought to play a role in prostate cancer progression, PRR signalling was explored to investigate potential additional benefits to PP2a stimulation. In terms of PRR signalling, the effect of the ApoE peptides on TLR and RIG-I signalling was assessed. The results demonstrated that the peptides decrease cell viability in a dose dependent manner in AR positive and AR negative cells. OP449 was shown to disrupt the progression of the cells through the cell cycle and successfully induce apoptosis in PC3 cells. The expression of SET oncoprotein was found to be up regulated in prostate cancer. COG112 and OP449 were shown to bind to SET and disrupt the protumourgenic SET-PP2A complex. Disruption of the SET-PP2A complex resulted in the upregulation of PP2A activity and negative regulation of Akt. COG112 and OP449 modulated the expression of TLRs 3 and 4 in AR negative cell lines. The peptides demonstrated an obstruction of downstream TLR signalling and were capable of hindering the response to TLR4 stimulation. Modulation of IκBα phosphorylation and p65 translocation was also observed. The results of this study support the need for further investigation into the use of ApoE mimetic peptides, namely OP449, in the treatment of advanced prostate cancer. The results exhibit OP449 to have multipurpose benefits and demonstrate that the ApoE peptide mimetics effectively target several pro tumorigenic signalling cascades in prostate cancer cells.

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Galway University Foundation

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Attribution-NonCommercial-NoDerivs 3.0 Ireland

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University of Galway Theses (PhD Theses)