title: The interaction between androgen receptor and PDGF-D in the radiation response of prostate carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology - Division of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Peter
authors.initials: P
authors.lastname: Paximadis
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Abdo J
authors.initials: AJ
authors.lastname: Najy
authors.affiliation: Department of Oncology - Division of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Hyeong-Reh
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D009570:Nitriles; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D008222:Lymphokines; D009570:Nitriles; C427493:PDGFD protein, human; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D010669:Phenylthiohydantoin; C540278:enzalutamide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: PDGF D; PTEN; prostate cancer; radiation