The Immunophilin Ligands Cyclosporin A and FK506 Suppress Prostate Cancer Cell Growth by Androgen Receptor-Dependent and -Independent Mechanisms

Abstract

The androgen receptor (AR) contributes to growth of prostate cancer even under conditions of androgen ablation. Thus, new strategies to target AR activity are needed. The AR interacts with the immunophilin FK506-binding protein 52 (FKBP52), and studies in the FKBP52 knockout mouse have shown that this protein is essential to AR activity in the prostate. Therefore, we tested whether the immunophilin ligand FK506 affected AR activity in prostate cancer cell lines. We also tested the hypothesis that the AR interacts with another immunophilin, cyclophilin 40 (Cyp40), and is regulated by its cognate ligand cyclosporin A (CsA). We show that levels of FKBP52, FKBP51, Cyp40, and a related co-chaperone PP5 were much higher in prostate cancer cells lines [(LNCaP), PC-3, and DU145] compared with primary prostate cells, and that the AR of LNCaP cells can interact with Cyp40. In the absence of androgen, CsA caused inhibition of cell growth in the AR-positive LNCaP and AR-negative PC-3 and DU145 cell lines. Interestingly, FK506 only inhibited LNCaP cells, suggesting a dependence on the AR for this effect. Both CsA and FK506 inhibited growth without inducing apoptosis. In LNCaP cells, CsA completely blocked androgen-stimulated growth, whereas FK506 was partially effective. Further studies in LNCaP cells revealed that CsA and FK506 were able to block or attenuate several stages of AR signaling, including hormone binding, nuclear translocation, and activity at several AR-responsive reporter and endogenous genes. These findings provide the first evidence that CsA and FK506 can negatively modulate proliferation of prostate cells in vitro. Immunophilins may now serve as new targets to disrupt AR-mediated prostate cancer growth.

FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

“…The Hsp90 inhibitor 17-AAG is a GA derivative with reduced hepatotoxicity in stage II clinical trials for cancers, including prostate cancer (34). 17-AAG and the immunophilin ligand FK506 each can inhibit prostate cancer cell growth in culture (21,30). Given our finding that in vitro assembly of the Hsp90-p23-FKBP51 superchaperone complex was prevented by inhibitors of Hsp90 and FKBP51 (Fig.…”

The 90-kDa Heat-shock Protein (Hsp90)-binding Immunophilin FKBP51 Is a Mitochondrial Protein That Translocates to the Nucleus to Protect Cells against Oxidative Stress

“…FKBP52 knock-out mice show phenotypes consistent with hormone insensitivity syndromes, in particular androgen insensitivity syndrome (20) and glucocorticoid insensitivity syndrome (21). In prostate cancer cell lines, increased levels of FKBP52 and FKBP51 were also reported, as well as an inhibitory effect of FK506 on androgenstimulated cell growth (22). Gene knock-out strategies revealed FKBP52, but not FKBP51, as an important facilitator of the physiological androgen receptor activity.…”

Identifying Molecular Chaperones as Therapeutic Targets for Cancer: A Mini Review

“…Besides above mentioned, there is a repertoire of chaperones that have been targeted for anticancer drug design [92,93]. Therefore, chaperones at the molecular level appear to cross the pathway of cancer progression at many levels and in many forms and some of their inhibitors have advanced in clinical trials.…”