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Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. Initially, prostate tumors are dependent on androgens for growth, and respond to androgen-deprivation therapy; however, the majority of prostate cancers treated with androgen ablation progress to an androgen-independent phenotype for which there is no established therapy. Filamin A (FlnA) is a 280kDa membrane-associated actin-binding protein consisting of an actin-binding domain followed by 24 100-residue repeats. FlnA is cleaved intracellularly to a 90kDa fragment consisting of repeats 16-24 (FlnA16-24). FlnA16-24 translocates to the nucleus and represses androgen receptor (AR) transcriptional activity. Here, we show that in the androgen-dependent human prostate cancer cell line LNCaP, the 90 kDa fragment translocates to the nucleus, whereas in an androgen-independent clone of LNCaP cells, C4-2, FlnA remains largely in the cytoplasm. Western blotting with an antibody to the C-terminal domain of FlnA which recognizes the 90 kDa fragment shows that C4-2 cells express decreased levels of FlnA16-24 compared to LNCaP. We hypothesize that failure of FlnA cleavage to FlnA16-24 results in the androgen independence of C4-2 cells. Unlike LNCaP cells, C4-2 cells are not growth arrested by the antiandrogen Casodex, reflecting their androgen-independent nature. Transfection of FlnA16-24, but not FlnA1-15, results in Casodex-induced growth arrest in C4-2 cells. The AR is a transcription factor that binds to androgen responsive elements (ARE) in the promoter region of target genes. P21Cip1/Waf1, an inhibitor of cyclin dependent kinases and cell cycle progression, contains an ARE in its promoter region. Casodex fails to induce p21Cip1/Waf1 expression in C4-2 cells. However, transfection with FlnA(16-24), but not FlnA(1-15) stimulated Casodex-induced p21 Cip1/Waf1 expression. These results suggest that FlnA16-24 reverses C4-2 cells to an androgen-dependent phenotype and that FlnA may be a suitable target for therapy in prostate cancer progression.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]