Role of the HSP90-Associated Cochaperone p23 in Enhancing Activity of the Androgen Receptor and Significance for Prostate Cancer

Abstract

Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or activity of AR coregulators affect trafficking and activation of the receptor. A key stage in AR signaling occurs in the cytoplasm, where unliganded receptor is associated with the heat shock protein (HSP)90 foldosome complex. p23, a key component of this complex, is best characterized as a cochaperone for HSP90 but also has HSP90-independent activity and has been reported as having differential effects on the activity of different steroid receptors. Here we report that p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). We show, for the first time, that AR and p23 can interact, perhaps directly, when HSP90 is not present in the same complex. The effects of p23 on AR activity are at least partly HSP90 independent because a mutant form of p23, unable to bind HSP90, nevertheless increases AR activity. In human prostate tumors, nuclear p23 was higher in malignant prostate cells compared with benign/normal cells, supporting the utility of p23 as a therapeutic target in prostate cancer.

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

“…p23 is able to increase the AR protein level and AR transcriptional activity which is independent of its role in the HSP90 foldosome complex30. Significantly, p23 expression is implicated in resistance to HSP90 inhibitors28, and plays a role in PCa metastasis.…”

“…p23 overexpression is induced on treatment with either androgens or anti-androgens and facilitates PCa cell motility; p23 knockdown inhibits the invasiveness of the PCa cell line LNCaP, suggesting an important role of p23 in PCa metastasis independent of its role as an HSP90 co-chaperone29. The expression of p23 increases AR protein level, AR ligand-binding activity and AR's target promoter-binding activity; most importantly, p23 functions to promote AR activity in an HSP90-independent mechanism involving the direct binding to AR30. p23 is also associated with an increased resistance to etoposide and doxorubicin in breast cancer cells31 along with elevated expression of a subset of estrogen-responsive genes32.…”

Molecular Chaperones and Co-chaperones as Therapeutic Targets for Cancer

“…Its co-chaperones are equally deemed as targets. P23 is among many of Hsp90 co-chaperone that is overexpressed in breast cancer [18], is involved in prostate cancer through androgen receptor activity [19] and is overexpressed in acute lymphoblastic leukemia where it inhibits chemotherapy-induced apoptosis [20].…”

17β-Estradiol and testosterone in sarcopenia: Role of satellite cells

“…Probably these differences in the chaperones involved are driven by specific domains in estrogen or androgen receptors. In view of that, these HSPs are able to interact with ERs or AR stabilizating them (Reebye et al, 2012;Zoubeidi et al, 2007).…”