title: Selenoprotein-P is down-regulated in prostate cancer, which results in lack of protection against oxidative damage.
abstract: BACKGROUND
  Oxidative stress plays a role in prostate cancer (PrCa) initiation and development. Selenoprotein-P (SepP; a protein involved in antioxidant defence) mRNA levels are down-regulated in PrCa. The main goal of our study was to assess whether SepP protects prostate cells from reactive oxygen species (ROS) in prostate carcinogenesis.
  
  
  METHODS
  Modification of SepP levels and ROS conditions in C3(1)/Tag-derived cell lines representing prostate epithelial neoplasia (PIN) lesions (Pr-111, with high SepP expression); and invasive tumors (Pr-14, with very low SepP expression).
  
  
  RESULTS
  Both Pr-111 and Pr-14 cells express ApoER2 (SepP receptor), which suggests that they may uptake SepP. Pr-14 cells had much higher ROS levels than Pr-111 cells and were highly sensitive to H(2)O(2)-mediated cytotoxicity. When SepP mRNA levels were knocked down with siRNAs in Pr-111 cells, a significant increase in ROS and cell growth inhibition upon H(2)O(2) exposure was found. Subsequent administration of purified SepP in the culture medium of these cells was able to rescue the original phenotype. Similarly, administration of SepP to Pr-14 cells was able to reduce ROS concentrations. Administration of flutamide decreased SepP mRNA levels whereas dihydrotestosterone or synthetic androgens induced SepP expression, indicating the importance of androgens for SepP expression. Immunohistochemical analysis using a PrCa tissue microarray further revealed that SepP protein was reduced in 60.8% prostate tumors compared to benign prostates.
  
  
  CONCLUSIONS
  Levels of SepP in prostate cells determine basal ROS levels and sensitivity to H(2)O(2)-induced cytotoxicity. Deregulation of SepP during prostate carcinogenesis may increase free radicals, thus promoting tumor development and de-differentiation.
authors: Division of Oncology, Center for Applied Medical Research, Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors: Oscar
authors: O
authors: Gonzalez-Moreno
authors: Noemi
authors: N
authors: Boque
authors: Miriam
authors: M
authors: Redrado
authors: Fermin
authors: F
authors: Milagro
authors: Javier
authors: J
authors: Campion
authors: Tobias
authors: T
authors: Endermann
authors: Kazuhiko
authors: K
authors: Takahashi
authors: Yoshiro
authors: Y
authors: Saito
authors: Raul
authors: R
authors: Catena
authors: Lutz
authors: L
authors: Schomburg
authors: Alfonso
authors: A
authors: Calvo
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D015536:Down-Regulation; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D018384:Oxidative Stress; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D051149:Selenoprotein P / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051149:Selenoprotein P; D005485:Flutamide; D006861:Hydrogen Peroxide