title: A critical role of the PTEN/PDGF signaling network for the regulation of radiosensitivity in adenocarcinoma of the prostate.
abstract: OBJECTIVE
  Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model.
  
  
  METHODS
  PTEN wild-type (PTEN+/+) and PTEN knockout (PTEN-/-) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN-/- cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen.
  
  
  RESULTS
  PTEN-/- cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN-/- cells demonstrated increased clonogenic survival in vitro compared to PTEN+/+, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN-/- cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN-/- cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference.
  
  
  CONCLUSIONS
  We propose that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study.
authors: Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan. Electronic address: mechristense@uwalumni.com.
authors: Michael
authors: M
authors: Christensen
authors: Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan.
authors: Abdo J
authors: AJ
authors: Najy
authors: Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan.
authors: Michael
authors: M
authors: Snyder
authors: Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan.
authors: Lisa S
authors: LS
authors: Movilla
authors: Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan.
authors: Hyeong-Reh Choi
authors: HR
authors: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D008222:Lymphokines / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000502:physiology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008222:Lymphokines; D009363:Neoplasm Proteins; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human