The interaction between androgen receptor and PDGF-D in the radiation response of prostate carcinoma.

Abstract

To determine the functional relationship between androgen receptor (AR) and PDGF D as it relates to the radiation response of PTEN-null prostate cancer (PCa) cells and the effect of enzalutamide on these interactions. Using murine PTEN-null prostate epithelial cell line and human prostate carcinoma LNCaP (PTEN-mutant) models, nuclear and cytosolic AR levels were determined by immunoblot analysis and the transcriptional activity of nuclear AR was assessed by RT-PCR analysis of its target genes with or without irradiation. Cell survival was evaluated by clonogenic assay or sulforhodamine B (SRB) assay upon irradiation in the absence or presence of the AR antagonist enzalutamide. PTEN loss resulted in upregulation of AR expression in a PDGF-D dependent manner and irradiation selectively increased the nuclear AR protein level and its activity in a murine cell model. When the functional significance of AR in cell survival was tested, treatment with enzalutamide resulted in radiosensitization of human LNCaP cells. Similarly to the murine model, PDGF-D overexpression increased the nuclear AR level and its transcriptional activity in LNCaP cells. PDGF-D over-expression was associated with radioresistance and enzalutamide treatment effectively reversed PDGF-D-mediated radioresistance in LNCaP cells. We have demonstrated that AR, a target of the PTEN and PDGF D-downstream signaling program, contributes to radiation resistance in human PCa cells. In addition, this study suggests that anti-androgens such as enzalutamide may serve as radiation sensitizers for the treatment of PCa patients, particularly so in patients with loss of PTEN or overexpression of PDGF-D.