Abstract
Current endocrine treatment for advanced prostate cancer does not result in a complete ablation of adrenal androgens. Adrenal androgens can be metabolized by prostate cancer cells, which is one of the mechanisms associated with progression to castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a steroidogenic enzyme that plays a crucial role in the conversion of adrenal androgen dehydroepiandrosterone (DHEA) into high-affinity ligands for the androgen receptor (testosterone [T] and dihydrotestosterone [DHT]). The aim of this study was to examine whether AKR1C3 could be used as a marker and therapeutic target for CRPC. AKR1C3 mRNA and protein levels were upregulated in CRPC tissue, compared with benign prostate and primary prostate cancer tissue. High AKR1C3 levels were found only in a subset of CRPC patients. AKR1C3 can be used as a biomarker for active intratumoral steroidogenesis and can be measured in biopsy or transurethral resection of the prostate specimens. DuCaP (a CRPC cell line that has high AKR1C3 expression levels) used and converted DHEA under hormone-depleted conditions into T and DHT. The DHEA-induced growth of DuCaP could be antagonized by indomethacine, an inhibitor of AKR1C3. This study indicates that AKR1C3 can be considered a therapeutic target in a subgroup of patients with high AKR1C3 expression.
Highlights
Androgen deprivation therapy (ADT), as a standard treatment for metastatic prostate cancer (PCa), is initially effective in reducing tumor burden, palliating symptoms and improving overall survival
Tissues were processed by step sectioning, and the samples for analysis were selected after histopathological confirmation of the tissue to be castration-resistant prostate cancer (CRPC), primary PCa, Benign prostatic hyperplasia (BPH) or normal prostate
Strong Aldo-keto reductase family 1 member C3 (AKR1C3) immunohistochemical staining was found in 34% (15 of 44) of CRPC cases (Figure 1C, image 2), and a moderate to weak staining was found in 50% (22 of 44) of CRPC cases (Figure 1C, image 3)
Summary
Androgen deprivation therapy (ADT), as a standard treatment for metastatic prostate cancer (PCa), is initially effective in reducing tumor burden, palliating symptoms and improving overall survival. Patients will eventually experience disease progression and develop castration-resistant prostate cancer (CRPC) within 1–3 years. CRPC patients have a poor prognosis, with a median survival of ~30 months [1]. On the basis of recent insights in the role of androgen receptor (AR) signaling in CRPC, several new therapeutic approaches are being tested in CRPC [2]. Abiraterone, a CYP17 inhibitor, was recently approved for chemotherapy-resistant CRPC, and a number of (other) drugs interfering with AR signaling are being tested in a clinical trial. There is no clear way to individualize these new thera-
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