11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored
| Autor: | Elzette Pretorius, Donita Africander, Jonathan L. Quanson, Maré Vlok, Meghan S. Perkins, Karl-Heinz Storbeck |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Cancer Treatment Gene Expression lcsh:Medicine urologic and male genital diseases Biochemistry Binding Analysis Prostate cancer 0302 clinical medicine Medicine and Health Sciences Testosterone lcsh:Science Multidisciplinary Organic Compounds Prostate Cancer Prostate Diseases Chemistry Prostatic Neoplasms Castration-Resistant Oncology Cell Processes Receptors Androgen Dihydrotestosterone Physical Sciences Androgens Steroids Cell Binding Assay Research Article Protein Binding medicine.drug Cell Physiology medicine.medical_specialty medicine.drug_class Urology 030209 endocrinology & metabolism Biology Research and Analysis Methods Response Elements Cell Growth 03 medical and health sciences Cell Line Tumor Internal medicine LNCaP Genetics medicine Animals Humans Androstenedione Chemical Characterization Cell Proliferation Cell growth Organic Chemistry lcsh:R Chemical Compounds Biology and Life Sciences Cancers and Neoplasms Cell Biology medicine.disease Androgen Hormones Cell Metabolism Biosynthetic Pathways Androgen receptor Genitourinary Tract Tumors 030104 developmental biology Endocrinology lcsh:Q |
| Zdroj: | PLoS ONE, Vol 11, Iss 7, p e0159867 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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