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The Androgen Receptor Directly Targets the Cellular Fas/FasL-Associated Death Domain Protein-Like Inhibitory Protein Gene to Promote the Androgen-Independent Growth of Prostate Cancer Cells

Department of Cancer Biology (S.G., H.W., Y.-F.W., Z.W.), The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Pathology (P.L., M.A.), New York University School of Medicine and New York Harbor Healthcare System, New York, New York 10010; and Department of Pathology (W.G., L.Z.), Memorial Sloan Kettering Cancer Center, New York, New York 10021

Address all correspondence and requests for reprints to: Zhengxin Wang, Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 173, Houston, Texas 77030-4009. E-mail: zhenwang{at}mdanderson.org.

Androgens provide survival signals to prostate epithelial cells, and androgen ablation induces apoptosis in the prostate gland. However, the molecular mechanisms of actions of the androgen-signaling pathway in these processes are not fully understood. Here, we report that androgens induced expression of the cellular Fas/FasL-associated death domain protein-like inhibitory protein (c-FLIP) gene, which is a potent inhibitor of Fas/FasL-mediated apoptosis. The androgen receptor was recruited to the promoter of the c-FLIP gene in the presence of androgens. We found that c-FLIP promoter contained multiple functional androgen response elements. In addition, we show that c-FLIP overexpression accelerated progression to androgen independence by inhibiting apoptosis in LNCaP prostate tumors implanted in nude mice. Our results suggest that the androgen receptor affects survival and apoptosis of prostate cells through regulation of the c-FLIP gene in response to androgens.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   R1881

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