Steroidogenic Enzymes and Stem Cell Markers Are Upregulated during Androgen Deprivation in Prostate Cancer

Abstract

Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent tumors. To study this hypothesis, we assessed the expression of several steroidogenic enzymes and stem cell markers in clinical PCa samples and cell cultures during androgen depletion. Gene expression profiles were determined by microarray or qRT-PCR. In addition, we measured cell viability and analyzed stem cell marker expression in DuCaP cells by immunocytochemistry. Seventy patient samples from different stages of PCa, and the PCa cell line DuCaP were included in this study. The androgen receptor (AR) and enzymes (AKR1C3, HSD17B2, HSD17B3, UGT2B15 and UGT2B17 ) that are involved in the metabolism of adrenal steroids were upregulated in castration resistant prostate cancer (CRPC). In vitro, some DuCaP cells survived androgen depletion, and eventually gave rise to a culture adapted to these conditions. During and after this transition, most of the steroidogenic enzymes were upregulated. These cells also are enriched with stem/progenitor cell markers cytokeratin 5 (CK5) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, putative stem/progenitor cell markers CK5, c-Kit, nestin, CD44, c-met, ALDH1A1, α2-integrin, CD133, ABCG2, CXCR4 and POU5F1 were upregulated in clinical CRPC. The upregulation of steroidogenic enzymes and stem cell markers in recurrent tumors suggests that cancer initiating cells can expand by adaptation to their T/DHT deprived environment. Therapies targeting the metabolism of adrenal steroids by the tumor may prove effective in preventing tumor regrowth.

Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: ‘Game Over’?

“…1) [19,26]. These preclinical findings are consistent with clinical observations that MET expression is higher in tumor samples from patients with CRPC compared with tumor samples from patients who have not yet undergone androgen-deprivation therapy [27], underlining that upregulation of the MET signaling correlated with the emergence of resistance to androgen suppression [28,29]. A possible explanation of this difference is resulted from preclinical studies showing that in vitro the AR negatively regulates the transcription and expression of MET in a ligand-dependent manner, leading to the inhibition of cell proliferation [29].…”

A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice

“…It has been previously shown that the AKR1C3 enzyme of the 550 steroid pathway is up-regulated in response to castration in clinical 551 patient samples [56]. AKR1C3 mediates the pro-androgenic 552 conversion of androstanediol and androstenedione to T [30,56]. 553 We confirm that this up-regulation also occurs in the LNCaP model 554 (Fig.…”

“…Conversely, 51 hypocholesterolemia generally inhibits prostatic tumor growth 52 [21]. Serum cholesterol levels are aligned with prostate cancer 53 progression, and explanations for these effects include: age- 54 related declines in the ability of prostate tissue to regulate 55 cholesterol [27]; activation of growth factor signal transduction 56 pathways [26]; and increased availability of substrate for local 57 steroid synthesis [21]. Thus, diet regimes that deplete serum 58 cholesterol may suppress CRPC tumor progression.…”

“…This effect of ADT may be enhanced by high-carbohydrate, 517 high-fat diets [28]. It has been previously shown that the AKR1C3 enzyme of the 550 steroid pathway is up-regulated in response to castration in clinical 551 patient samples [56]. AKR1C3 mediates the pro-androgenic 552 conversion of androstanediol and androstenedione to T [30,56].…”

In vitro model systems to study androgen receptor signaling in prostate cancer

“…Moreover, given their upregulation of AR and numerous enzymes involved in the metabolism of adrenal steroids following androgen deprivation, DuCaPs may represent an ideal in vitro model system to study intratumoral de novo androgen synthesis, a key mechanism underlying progression to CR-PCa ( Fig. 2; Locke et al 2008, Pfeiffer et al 2011.…”