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: Oscar Gonzalez-Moreno, Noemi Boque, Miriam Redrado, Fermin Milagro, Javier Campion, Tobias Endermann, Kazuhiko Takahashi, Yoshiro Saito, Raul Catena, Lutz Schomburg, Alfonso Calvo
• Journal: The Prostate (Prostate) Vol. 71 Issue 8 Pg. 824-34 (Jun 01 2011) ISSN: 1097-0045 [Electronic] United States
• PMID: 21456065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Androgen Antagonists
• RNA, Small Interfering
• Reactive Oxygen Species
• Selenoprotein P
• Flutamide
• Hydrogen Peroxide

Topics

• Androgen Antagonists (pharmacology)
• Carcinoma (metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Down-Regulation
• Flutamide (pharmacology)
• Humans
• Hydrogen Peroxide (toxicity)
• Male
• Oxidative Stress
• Prostatic Intraepithelial Neoplasia (metabolism, pathology)
• Prostatic Neoplasms (metabolism, pathology)
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism, toxicity)
• Selenoprotein P (antagonists & inhibitors, metabolism)