Hsp27 promotes IGF-1 survival signaling in prostate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-03, Vol.70 (6), p.2307-2317
• Main Authors: Zoubeidi, Amina, Zardan, Anousheh, Wiedmann, Romina M., Locke, Jennifer, Beraldi, Eliana, Fazli, Ladan, Gleave, Martin E.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-3252

Hsp27 is highly expressed in castrate-resistant prostate cancer. While its overexpression confers resistance to androgen ablation and chemotherapy, the mechanisms by which Hsp27 inhibits treatment-induced apoptosis are incompletely defined. Castrate-resistance often correlates with increased activity of autocrine and/or paracrine growth/survival stimulatory loops including the MAPK and Akt pathways and insulin-like growth factor (IGF) axis components. Since Hsp27 can be activated by both MAPK and Akt pathways, it is possible that interactions between IGF-1 signaling and Hsp27 phospho-activation function to promote castrate resistant progression. Here we report that Hsp27 expression and phosphorylation levels correlate with IGF-1 signaling and castrate resistant progression in human prostate cancer specimens and cell lines. IGF-1 induces Hsp27 phosphorylation in a time- and dose-dependent manner via p90Rsk, which directly interacts with and phosphorylates Hsp27 in vitro and in vivo . Conversely, p90Rsk inhibition using siRNA or a mutant dominant negative abolishes IGF-1 induced Hsp27 phosphorylation. Hsp27 over-expression increases IGF-1-induced phosphorylation of Erk, p90Rsk and Akt. Conversely, Hsp27 knockdown abrogates IGF-1 induced phosphorylation of Erk, p90Rsk and Akt, thereby destabilizing Bad/14-3-3 complexes and increasing apoptotic rates. These data elucidate interactions between Hsp27 phosphorylation and the IGF-1R signaling pathway and support targeting Hsp27 as a therapeutic strategy for castrate-resistant prostate cancer.