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MP55-17 EFFECT OF EPIGENETIC MODIFICATION AND IMMUNOMODULATION ON MURINE PROSTATE CANCER AND DENDRITIC CELLS
- Source :
- Journal of Urology. 193
- Publication Year :
- 2015
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2015.
-
Abstract
- common precursor of testosterone (T) and dihydrotestosterone (DHT). We reported 5a-androstane-3b,17b-diol (3b-diol), which is inactive androgen metabolized from DHT, can be converted back to DHEA and finally to DHT. In this pathway, 3b-hydroxysteroid dehydrogenase (3bHSD) is the key enzyme for the conversion from DHEA and epiandrosterone (epiAND) to DHT, and Rui et al. reported abiraterone inhibited 3b-HSD in CRPC. We examined the effect of CYP17 inhibitors on the intracrine back-conversion pathway induced by 3b-diol in prostate cancer cells. METHODS: LNCaP cells were incubated in the presence of 3bdiol or DHEA 10nmol/L with or without CYP17 inhibitors (abiraterone, ketoconazole, or orteronel) 10nmol/L. In all experiments, LNCaP cells were incubated without any androgens and CYP17 inhibitors as a control (CTRL). After incubation, PSA levels in the media were determined by enzyme immunoassay, and androgen levels in media were measured by LC-MS/MS. RESULTS: By adding DHEA or 3b-diol in media, PSA levels were increased (p 1⁄4 0.013 and p < 0.001, respectively). 3b-diol highly activated AR about five-times compared to DHEA. Inhibition of PSA secretion by abiraterone, ketoconazole and orteronel was found in the presence of DHEA (p < 0.001, p 1⁄4 0.002, and p 1⁄4 0.017, respectively). 3b-diol-induced PSA accumulation in media was inhibited by abiraterone, not ketoconazole or orteronel. By adding 3b-diol in medium, DHEA, androstenediol (A-diol), androstendione (A-dione), T, and DHT levels were increased compared to CTRL. In the media with 3b-diol and abiraterone, A-dione, T, DHT, and 5a-androstanedione (5a-A-dione) levels were decreased, DHEA, 5-diol, and epiAND levels increased compared to 3b-diol only. CONCLUSIONS: AR was highly activated by 3b-diol compared to DHEA through the conversion of 3b-diol to DHT by way of epiAND and 5a-A-dione, which abiraterone blocked by inhibiting 3b-HSD. Abiraterone has a potential to inhibit the intracrine back-conversion pathway.
- Subjects :
- endocrine system
Intracrine
medicine.medical_specialty
medicine.drug_class
business.industry
Urology
Androstenediol
urologic and male genital diseases
Androgen
chemistry.chemical_compound
Endocrinology
chemistry
Dihydrotestosterone
Internal medicine
LNCaP
polycyclic compounds
medicine
Orteronel
Ketoconazole
business
hormones, hormone substitutes, and hormone antagonists
Testosterone
medicine.drug
Subjects
Details
- ISSN :
- 15273792 and 00225347
- Volume :
- 193
- Database :
- OpenAIRE
- Journal :
- Journal of Urology
- Accession number :
- edsair.doi...........c8f6279b84a7a52446fa430202a406e2