title: 11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored.
abstract: Dihydrotestosterone (DHT) is regarded as the most potent natural androgen and is implicated in the development and progression of castration resistant prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal androgen precursors, DHEA and androstenedione. Recent studies have shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the androgen dependent prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide androgens capable of inducing androgen-dependant gene expression and cell growth, and that these steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC.
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch, 7602, South Africa.
authors.forename: Elzette
authors.initials: E
authors.lastname: Pretorius
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch, 7602, South Africa.
authors.forename: Donita J
authors.initials: DJ
authors.lastname: Africander
authors.affiliation: Proteomics Unit, Central Analytical Facility, University of Stellenbosch, Stellenbosch 7602, South Africa.
authors.forename: Maré
authors.initials: M
authors.lastname: Vlok
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch, 7602, South Africa.
authors.forename: Meghan S
authors.identifier: http://orcid.org/0000-0002-7046-8747
authors.initials: MS
authors.lastname: Perkins
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch, 7602, South Africa.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Quanson
authors.affiliation: Department of Biochemistry, University of Stellenbosch, Stellenbosch, 7602, South Africa.
authors.forename: Karl-Heinz
authors.identifier: http://orcid.org/0000-0003-1669-6383
authors.initials: KH
authors.lastname: Storbeck
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism; D020218:Response Elements; D013739:Testosterone / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C586666:11-ketodihydrotestosterone; D000728:Androgens; D011944:Receptors, Androgen; D013739:Testosterone; C003600:11-ketotestosterone