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

Abstract

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.

FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

“…FLIP regulation by androgens has been demonstrated in our previous in vivo studies (Nastiuk et al, 2003) and in vitro by others (Gao et al, 2005). Moreover, FLIP overexpression correlates with progression to androgen independence (Gao et al, 2005).…”

“…FLIP regulation by androgens has been demonstrated in our previous in vivo studies (Nastiuk et al, 2003) and in vitro by others (Gao et al, 2005). Moreover, FLIP overexpression correlates with progression to androgen independence (Gao et al, 2005). FLIP is regulated by PI3K/Akt signaling (Panka et al, 2001) and in endothelial cells, FLIP is negatively regulated by FOXO3a (Skurk et al, 2004).…”

Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis

“…A critical step in apoptosis that follows the activation of death receptor by TRAIL is the recruitment of FADD downstream that results in the activation of caspases leading to cell death. Androgens have been shown to induce expression of the c-FLIP gene, which is a potent inhibitor of Fas/ FasL-mediated apoptosis (Gao et al, 2005). This largely explains the fact that LNCaP cells are resistant to TRAIL-mediated apoptosis compared to their AR negative counterpart PC3 (Figure 1a).…”

Androgen Action During Prostate Carcinogenesis

“…In prostate cancer cells, increased c-FLIP expression is associated with increased resistance to death receptor-induced apoptosis (99,100). LNCaP xenografts overexpressing c-FLIP are also resistant to castrationinduced growth inhibition, suggesting a role of c-FLIP in the development of CRPC (99). It has also been observed that both c-FLIP mRNA and protein levels are reduced during progression to CRPC in animal models (101,102).…”

“…It has also been observed that both c-FLIP mRNA and protein levels are reduced during progression to CRPC in animal models (101,102). C-FLIP is directly regulated by androgens via a cluster of four AREs within a 156-bp region downstream from the transcription start site (99). Accordingly, both c-FLIP mRNA and protein levels are reduced following castration of rats in multiple tissues, including dorsolateral prostate and seminal vesicles (100).…”