The Role of Carboxypeptidase-D in Prostate Cancer Growth and Progression

Prostate cancer (PCa) is the most frequently diagnosed cancer among men, afflicting one in seven Canadian men in his lifetime. PCa is typically treated by surgery and radiation, and may be combined with androgen ablation therapy. The latter aims to reduce serum androgens and to inhibit the androgen receptor in PCa cells. Although PCa often responds well initially to androgen ablation therapy, there is a high risk of recurrence since most patients become refractory to androgen withdrawal. The prognosis for recurrent PCa is poor as treatment options are limited, and may be ineffective. Our proposed research is on the enzyme carboxypeptidase-D (CPD) as a potential therapeutic target for PCa. We have recently reported that CPD acts to promote survival of human PCa cells in culture. In screening excised prostate tissues from men diagnosed with PCa, we have observed that CPD levels are highly elevated in primary, high-grade PCa and in recurrent PCa, as compared to low levels in normal or benign prostate tissues. Therefore, our studies implicate a role for CPD in the growth and survival of PCa cells, and in the progression of PCa tumours. We have also reported that CPD levels are increased in PCa cells by androgens and prolactin, suggesting that androgen ablation alone is insufficient to block CPD action. Our proposed study will fully elucidate regulation of the CPD gene, and how the CPD protein acts to promote growth/survival of PCa cells in culture, and in PCa tumours implanted in a mouse model. Our study will give a greater understanding as to how CPD contributes to the pathological progression of PCa, and is an essential step towards the discovery of new and more effective hormone ablation therapies for the treatment and/or management of this disease.