Abstract
Prostate cancer is an androgen receptor (AR)-dependent malignancy at initiation and progression, therefore hormone therapy is the primary line of systemic treatment. Despite initial disease regression, tumours inevitably recur and progress to an advanced castration-resistant state a major feature of which is metastasis to the bone. Up-regulation of AR cofactors and chaperones that overcome low hormone conditions to maintain basal AR activity has been postulated as a mechanism of therapy relapse.p23, an essential component of the apo-AR complex, acts also after ligand binding to increase AR transcriptional activity and target gene expression, partly by increasing chromatin-loaded holo-receptor-complexes. Immunohistochemical studies have demonstrated increased p23 expression in advanced prostate cancer. Here, we further characterise p23 roles in AR signalling and show that it modulates cytosolic AR levels in the absence of hormone, confirming a chaperoning function in the aporeceptor complex and suggesting p23 upregulates AR signalling at multiple stages. Moreover, p23 protein levels significantly increased upon treatment with not only androgen but also clinically relevant anti-androgens. This was in contrast to the HSP90 inhibitor 17-AAG, which did not modulate expression of the cochaperone – important given the HSP90-independent roles we and others have previously described for p23.Further, we demonstrate p23 is implicated in prostate cancer cell motility and in acquisition of invasiveness capacity through the expression of specific genes known to participate in cancer progression. This may drive metastatic processes in vivo since analysis of prostate tumour biopsies revealed that high nuclear p23 significantly correlated with shorter survival times and with development of metastases in patients with lower grade tumours. We propose that increased p23 expression may allow cells to acquire a more aggressive phenotype, contributing to disease progression, and that p23 is a plausible secondary target in combination with HSP90 inhibition as a potential therapy for advanced prostate cancer.
Highlights
The molecular chaperone p23 is ubiquitously expressed and highly conserved from yeast to humans (Felts and Toft, 2003; Garcia-Ranea et al, 2002)
We demonstrate p23 is implicated in prostate cancer cell motility and in acquisition of invasiveness capacity through the expression of specific genes known to participate in cancer progression
We have previously shown that increasing levels of p23 by ectopic expression significantly enhances androgen receptor (AR) transcriptional activity and, decreasing p23 levels using siRNA decreases it (Reebye et al, 2012)
Summary
The molecular chaperone p23 is ubiquitously expressed and highly conserved from yeast to humans (Felts and Toft, 2003; Garcia-Ranea et al, 2002) It was first characterised as a component of the progesterone receptor (PR) complex but is an intrinsic component of several other steroid receptor (SR) hetero-complexes, exerting distinct effects on different receptors (Freeman and Yamamoto, 2002; Hutchison et al, 1995; Nair et al, 1996; Reebye et al, 2012). We have previously shown nuclear p23 to enhance AR activity and binding to chromatin, critical steps for AR signalling and prostate cancer development, and to be increased with tumour grade (Reebye et al, 2012). In combination with our observations regarding the positive effects of p23 upon AR stabilisation and signalling, and on cell aggressiveness and motility, this leads us to postulate that inhibiting p23 in combination with HSP90 could be an effective therapeutic combination against prostate cancer
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
