title: A designed cell-permeable aptamer-based corepressor peptide is highly specific for the androgen receptor and inhibits prostate cancer cell growth in a vector-free mode.
abstract: The repression of the androgen receptor (AR) activity is a major objective to inhibit prostate cancer growth. One underlying mechanism for efficient hormone therapy is based on corepressors that inactivate the AR. In line with this, castration-resistant prostate cancer is associated with malfunction or reduced corepressor action. To overcome this, the overexpression of endogenous corepressors, however, affects many other transcription factors. Therefore, an AR-specific corepressor could be of advantage. Using a yeast peptide aptamer two-hybrid screen with the full-length human AR, we identified a short amino acid-stretch that binds specifically to the human AR in yeast and in mammalian cells and not to the closely related progesterone or glucocorticoid receptors. Furthermore, fused to a silencing domain, this aptamer-based corepressor (AB-CoR) exhibits corepressor activity by inhibiting both the AR-mediated transactivation and expression of the AR target gene PSA. Furthermore, stable expression of the AB-CoR inhibits growth of human LNCaP prostate cancer cells. Moreover, we generated a cell-permeable AB-CoR by fusing a protein transduction domain to establish a vector-free transport system. Treatment of LNCaP cells with the bacterially expressed and affinity-purified cell-permeable AB-CoR peptide resulted in a significant inhibition of both AR-mediated transactivation and prostate cancer cell proliferation. Thus, generation of a novel AR-specific aptamer-based corepressor may present a vector-free inhibition of AR-dependent prostate cancer growth as a novel approach.
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany. aria.baniahmad@mti.uni-jena.de
authors.forename: Christina A
authors.initials: CA
authors.lastname: Reeb
authors.forename: Claudia
authors.initials: C
authors.lastname: Gerlach
authors.forename: Maria
authors.initials: M
authors.lastname: Heinssmann
authors.forename: Ina
authors.initials: I
authors.lastname: Prade
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Ceraline
authors.forename: Julia
authors.initials: J
authors.lastname: Roediger
authors.forename: Daniela
authors.initials: D
authors.lastname: Roell
authors.forename: Aria
authors.initials: A
authors.lastname: Baniahmad
mesh_terms: D052158:Aptamers, Peptide / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D010539:Permeability; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D052158:Aptamers, Peptide; D056970:Co-Repressor Proteins; D011944:Receptors, Androgen