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) residues in an AR- and p38 kinase-dependent manner. After this androgen-induced, non-nuclear phospho-activation, Hsp27 displaces Hsp90 from a complex with AR to chaperone AR into the nucleus and interact with its response elements to enhance its genomic activity. Inhibition of Hsp27 phosphorylation, or knockdown using the antisense drug OGX-427, shifted the association of AR with Hsp90 to MDM2, increased proteasome-mediated AR degradation, decreased AR transcriptional activity, and increased prostate cancer LNCaP cell apoptotic rates. OGX-427 treatment of mice bearing LNCaP xenografts transfected with an androgen-regulated, probasin-luciferase reporter construct resulted in decreased bioluminescence and serum PSA levels as pharmacodynamic readouts of AR activity, as well as AR, Hsp27, and Hsp90 protein levels in LNCaP tumor tissue. These data identify novel nongenomic mechanisms involving androgen, AR, and Hsp27 activation that cooperatively interact to regulate the genomic activity of AR and justify further investigation of Hsp27 knockdown as an AR disrupting therapeutic strategy in prostate cancer.
Highlights
The androgen receptor (AR), a ligand-dependent transcription factor and member of the class I subgroup of the nuclear receptor superfamily, plays a key role in prostate carcinogenesis and progression
OGX-427–induced knockdown of heat-shock protein 27 (Hsp27) was associated with decreased apoptotic rates in R1881treated cells, as measured by fluorescence-activated cell sorting (FACS) and poly(ADP ribose)polymerase (PARP) cleavage (Fig. 1B and C)
We explored whether Hsp27 forms a complex with AR on the Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-2057 (ARE) of the prostate-specific antigen (PSA) promoter using Chromatin immunoprecipitation (ChIP) assay in LNCaP cells FR1881. h-Actin fragment was amplified as control
Summary
The androgen receptor (AR), a ligand-dependent transcription factor and member of the class I subgroup of the nuclear receptor superfamily, plays a key role in prostate carcinogenesis and progression. (ARE) in the transcriptional regulatory regions of target genes [1, 2] In addition to this transcriptional genomic action, androgens and other steroid hormones like progesterone and estrogen can exert rapid nongenomic effects that are not mediated through nuclear receptors, but rather initiated at the plasma membrane, presumably through surface receptors [3, 4]. Androgens rapidly stimulate Raf-1 and Erk-2, both components of the MAPK signaling cascade [5], suggesting that androgenstimulated MAPK activation occurs via nongenomic mechanisms. This nongenomic action of androgen can influence classic genomic AR activity, including modulation of AR by coactivators [7]. AR is found in a large protein complex with p85a-PI3K and Src, both required for androgen-stimulated PI3K/Akt activation [3, 10]
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