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TNF-α induces a range of biological responses associated with apoptosis/survival in many cells. TNF-α stimulates death receptor mediated signaling pathway that activates a downstream protease cascade leading to cell death. On the other hand, TNF-α induces a receptor mediated survival pathway involving activation of a series of protein kinases and NFκB. TNF-α has been shown to be associated with cancer progression. In prostate cancer patients, especially in recurrent tumor patients, the serum level of TNF-α is elevated and is closely correlated with the extent of disease state. Such result suggests that TNF-α is associated with the progression of prostate cancer. Nevertheless, very limited number of studies has been done regarding the effect of TNF-α on AR signaling in prostate cancer cells.

We tried to examine whether TNF-α affects AR signaling pathway in LNCaP prostate cells. We found that TNF-α stimulates nuclear translocation of AR. TNF-α increases transcriptional activity of AR significantly in androgen depleted condition. The mRNA and protein level of AR regulated PSA was increased upon TNF-α treatment. The effect of TNF-α on acetylation level of AR was examined by immunoprecipitation study using antibody against acetylated lys. We found that AR acetylation is increased by TNF-α treatment in the absence of androgen. In addition, TNF-α treatment increased CBP/p300 expression in LNCaP cells in the absence of androgen.

Taken together our results suggest that TNF-α acts as a non-steroidal activator of AR signaling in LNCaP cells, especially in the absence of androgen. The acetylation of AR signaling by TNF-α may be mediated through activation of CBP/p300.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA