Endocrine Abstracts

Prostate cancer cells show a variable expression of androgen receptor (AR). Its function is influenced by coregulatory proteins that may interact with the N-terminal and/or ligand-binding domain. Cofactor expression and function may be altered in prostate cancer. Studies by my group were focused on the transcriptional integrator CBP and its functional homologue p300 in prostate cancer. We found that CBP selectively potentiates activation of the AR by the non-steroidal anti-androgen hydroxyflutamide. Expression of CBP is inhibited by the synthetic androgen R1881 and interleukin-6 (IL-6). Immunohistochemical studies revealed that most prostate cancers, including therapy-resistant ones, express CBP. It is assumed that a high expression of CBP in tumours from patients who failed endocrine therapy is a consequence of androgen deprivation therapy.

IL-6 is a multifunctional cytokine that regulates proliferation, apoptosis, angiogenesis, and expression of secretory proteins in prostate cells. AR activity is up-regulated by IL-6. Proliferation of androgen-sensitive LNCaP cells is inhibited by IL-6. However, during prolonged treatment of LNCaP cells with IL-6, a subline has been generated (LNCaP-IL-6+). This subline acquires a growth advantage in vitro and in vivo. These cells show up-regulated expression of cyclin-dependent kinases 2 and 4 and down-regulation of tumour suppressors p27 and pRb. There was no phosphorylation of STAT3 in cells generated in the presence of IL-6. In contrast, inhibition of the mitogen-activated protein kinase pathway resulted in a partial retardation of tumour growth. Interestingly, the AR target gene prostate-specific antigen was induced by p300 in that subline.

Taken together, these results demonstrate that (a) CBP and its functional homologue p300 are important coactivators in advanced prostate cancer and (b) IL-6, a cytokine whose levels are elevated in prostate tumour tissues and patients´ sera, is a target for novel therapies in prostate cancer.