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The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and phosphatidylinositol 3-kinase/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone-refractory prostate disease. Our initial investigations show that the naturally occurring organoselenium compound selenomethionine (SM) and the synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) can inhibit human prostate cancer cell viability; however, in contrast to SM, p-XSC is active at physiologically relevant doses. In the current investigation, we show that p-XSC, but not an equivalent dose of SM, alters molecular targets and induces apoptosis in androgen-responsive LNCaP and androgen-independent LNCaP C4-2 human prostate cancer cells. p-XSC effectively inhibits AR expression and transcriptional activity in both cell lines. p-XSC also decreases Akt phosphorylation as well as Akt-specific phosphorylation of the AR. Inhibition of Akt, however, does not fully attenuate p-XSC-mediated downregulation of AR activity, suggesting that inhibition of AR signaling by p-XSC does not occur solely through alterations in the phosphatidylinositol 3-kinase/Akt survival pathway. Our data suggest that p-XSC inhibits multiple signaling pathways in prostate cancer, likely accounting for the downstream effects on proliferation and apoptosis.

1,4-Phenylenebis(Methylene)Selenocyanate, but Not Selenomethionine, Inhibits Androgen Receptor and Akt Signaling in Human Prostate Cancer Cells