Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP

Abstract

It has been suggested in many studies that combined treatment with chemotherapeutic agents and apoptosisinducing ligands belonging to TNFR family is a more effective strategy for cancer treatment. However, the role of androgen regulation of TNFR family-induced apoptosis in prostate cancer is poorly understood. In this study, we investigated the dose-dependent effects of androgen on TNF-a and TRAIL-mediated apoptosis in LNCaP. To investigate the interaction between the androgen receptor (AR) and the caspase-2 gene, chromatin immunoprecipitation analysis was used, and we are the first to identify that AR interacts in vivo with an androgen-responsive elements in intron 8 of caspase-2 gene. We have found that DHT inhibited apoptosis in dose-dependent manner. There is a direct, androgen-dependent correlation between the levels of activated Akt and caspase activation after treatment with TNF-a and TRAIL. We have also found that there are at least two different regulatory mechanisms of p53 expression by androgen: at the gene and protein levels. At the same time, the level of AR was found to be higher in LNCaP-si-p53 compared to LNCaP-mock cells. These data indicate that there is a mutual regulation of expression between p53 and AR. Our study suggests that androgen-dependent outcome of apoptotic treatment can occur, at least in part, via the caspase-2, Akt and p53-mediated pathways.

Phellinus linteus activates different pathways to induce apoptosis in prostate cancer cells

“…It has also been shown that activated caspase 2 can directly cause the cleavage of BID (Harvey et al, 1997;Droin et al, 2001). In addition, studies have demonstrated that caspase 2, upon different apoptotic stimulations, re-distributes to the nuclei or other subcellular membrane compartments to participate in the execution of the cell death programme (Mancini et al, 2000;Chae et al, 2004;Rokhlin et al, 2005). Our results here demonstrate the interconnection between AR and caspase 2 in the regulation of PL-induced apoptosis in prostate cancer cells.…”

“…It has been reported that the AR, by repressing the cis-element of the caspase 2 promoter, regulates caspase 2 expression (Rokhlin et al, 2005). Our results presented above indicate the involvement of AR or caspase 2 in PL-induced apoptosis in LNCaP cells.…”

Inhibition of Akt signaling by the lignan matairesinol sensitizes prostate cancer cells to TRAIL-induced apoptosis

“…Together these results imply that MAT inhibits Akt activity and thereby sensitizes LNCaP cells to TRAILinduced apoptosis. In fact, the mechanism underlying LNCaP insensitivity to death receptor stimulation has been shown earlier to involve the PI3K/Akt survival pathway Nesterov et al, 2001;Rokhlin et al, 2002Rokhlin et al, , 2005. The constitutive activation of the PI3K/Akt-pathway observed in many cancer Lignans sensitize prostate cancer cells to TRAIL E Peuhu et al forms can be related, for example, to the loss of PTEN, a lipid phosphatase that negatively regulates the pathway (Vlietstra et al, 1998).…”

“…The LNCaP cells have a high constitutive Akt activity, which appears to protect the cells from TRAIL-induced apoptosis Nesterov et al, 2001;Rokhlin et al, 2002Rokhlin et al, , 2005. To analyse the possibility that MAT would sensitize LNCaP cells to TRAIL by inhibiting the PI3K/Akt-pathway, we first analysed whole cell lysates after 1 h of MAT treatment for the levels of phosphorylated Akt (Figure 5a).…”

Androgen receptor and prostate cancer

“…54 Significantly, AR mutation can directly promote CaP cell growth and suppress the protective role of p53 pointing to tight regulatory loop between AR and p53. 55,56 Ultimately all recurrent disease progresses to a phase in which it is androgen depletion independent. An interesting phenomenon occurs in which antiandrogens begin to act as agonists.…”