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Characterization of the Truncated Androgen Receptor Generated by Calpain-Dependent Proteolysis in Prostate Cancer

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Annual summary, 1 Aug 2008-31 Jul 2009

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Androgen ablation therapy is effective in treating androgen-dependent prostate tumors however, tumors that can proliferate in castrate levels of androgen eventually arise. We previously reported that in CWR22Rv1 Rv1 cells, the protease calpain 2 can cleave the androgen receptor AR into a constitutively active 80 KDa low molecular weight LMW form. In this study, we further dissect the mechanisms that produce the AR LMW forms using Rv1 cells and the related CWR22-R1 R1 cells. The 39 a.a. insertional mutation in Rv1 cells sensitizes this AR E3DM-AR calpain 2 proteolysis. R1 cells encode the same AR molecule as the parental CWR22 xenograft. Using anti-calpain 2 siRNA and calpeptin, we find that calpain 2 plays a role in the generation of the LMW-AR in R1 cells. Furthermore, LMW-AR expression is regulated by the activation of calpain 2 by Extracellular Signal-Regulated Kinases 12 ERK. Inhibition of ERK phosphorylation or siRNA-mediate decrease of ERK expression reduces LMW-AR levels in R1 cells. Conversely, activation of the MAPK pathway and increased ERK phosphorylation results in increased levels of LMW-AR. Finally, analyses of human tumor samples found that LMW-AR levels are higher in tumors that have an increased calpaincalpastatin ratio andor increased levels of phospho-ERK pERK, suggesting that a higher calpaincalpastatin ratio collaborates with activation of the MAP kinase pathway to promote the generation of the LMW-AR. Furthermore, cellular localization analysis of AR shows that the LMW-AR is the predominant form 90 present in the nucleus in Rv1 cells cultured in the absence of androgen, allowing us to study the chromosomal binding sites of LMW-AR using chromatin immunoprecipitation ChIP combined with DNA microarray analysis Chip-on-Chip.

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  • Medicine and Medical Research

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