The co‐chaperone p23 promotes prostate cancer motility and metastasis

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.

Tissue proteomics outlines AGR2 AND LOX5 as markers for biochemical recurrence of prostate cancer

“…In addition, it is reported to be an enhancer of androgen receptor activity. It is involved in AR binding to chromatin, which is a critical step in AR signalling and PCa development [32, 33]. Further validation is still required, using both quantitative mass spectrometry and immunohistochemistry, to confirm a potential role of this protein in PCa diagnosis and prognosis.…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Besides CHIP, other protein partners of HSP90 may somehow be involved in EMT and cancer stemness-associated events. For instance, the co-chaperone p23 was shown to contribute to the acquisition by prostate cancer cells of a more aggressive (CSC-resembling) phenotype with higher cell motility and pronounced capacity for invasion and metastasis formation [90]. There was a report that the co-chaperone Hop (HSP70/HSP90 organizing protein) and its complexes with cellular prion protein maintain the stemness in gliomas by ensuring proliferation and self-renewal in glioma SCs [91].…”

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…Hsp27 expression also favors metastasis though its effects on a process known as the epithelial-mesenchymal transition, in which cells switch from a compact shape to a spindle shape and gain enhanced cell motility [67–69]. In addition, elevated co-chaperone levels also promote (prostate) cancer; increased levels of the Hsp90 co-chaperone p23 increases metastasis in prostate cancer[70]. The ability of HSPs to respond to and protect cells from stress may also permit metastasizing cells to survive the trauma involved in passage through blood vessels.…”