Cooperative Interactions between Androgen Receptor (AR) and Heat-Shock Protein 27 Facilitate AR Transcriptional Activity

Abstract

Androgen receptor (AR) transactivation is known to enhance prostate cancer cell survival. However, the precise effectors by which the prosurvival effects of androgen and AR drive prostate cancer progression are poorly defined. Here, we identify a novel feed-forward loop involving cooperative interactions between ligand-activated AR and heat-shock protein 27 (Hsp27) phospho-activation that enhance AR stability, shuttling, and transcriptional activity, thereby increasing prostate cancer cell survival. Androgen-bound AR induces rapid Hsp27 phosphorylation on Ser 78 and Ser 82

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

“…Additionally, 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG); retaspimycin hydrochloride (IPI-504), two Hsp90 inhibitors, provided no benefit to CRPC patients (55,56). The poor therapeutic effect of Hsp90 inhibitors may be the consequence of inhibiting widespread client proteins and may thereby result in activation of oncogenic signaling pathways such as Src and co-chaperone Hsp27 up-regulation (57,58). Inhibition of Cdc37, a co-chaperone of Hsp90 that is overexpressed in cancer cells, may represent a better drug target in cancers (59).…”

The Roles of HSP27 and Annexin II in Resistance to UVC-Induced Cell Death: Comparative Studies of the Human UVC-Sensitive and -Resistant Cell Lines RSa and APr-1

“…20,21) Taking this together with the results presented in Fig. 1, we hypothesized that HSP27 acts as a molecular chaperone for annexin II in resistance to UVC-induced cell death, thus regulating annexin II expression after UVC irradiation.…”

“…21) In the AP r -1 cells, the formation of a complex between HSP27 and annexin II increased in the nuclear fraction after UVC irradiation. 12) Annexin II is reported to function mainly in the cytoplasm, 13) but part of the protein localizes to and functions in the nucleus.…”

“…The mechanisms underlying the involvement of annexin II in UVC resistance and by which HSP27 regulates the levels of annexin II protein remain unknown. Recently, HSP27 has been reported to increase the stability of the Her2 protein 20) and androgen receptor 21) by affording protection against proteasome-mediated degradation. In this study, the changes in annexin II protein levels were a result of the balance between synthesis and degradation activities.…”

Kinase joins the chaperone club: Androgen-regulated kinome reveals choline kinase alpha as a potential drug target in prostate cancer

“…3 Consistent with this concept, targeting of HSPs and kinases in preclinical models inhibits AR function and PCa tumor growth. 4,5 While these diverse resistance mechanisms highlight the reliance of PCa on AR signaling, there is a critical need to identify therapeutic targets that regulate AR function as well as key downstream effector pathways.…”