Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC. Cancer Res; 70(3); 1256–64
Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.
High glucocorticoid concentrations are accompanied by metabolic side effects such as high plasma triglyceride (TG) concentrations. Liver, brown adipose tissue (BAT) and white adipose tissue are important regulators of plasma TG. Exposure to 4°C reduces plasma TG concentrations, and we therefore aimed to study the interaction between glucocorticoid excess and 24 hours of exposure to 4°C on lipid metabolism. For this, mice were implanted with 50-mg corticosterone or control pellets and housed for 24 hours at 23°C or 4°C 1 week later, after which various aspects of TG metabolism in liver, BAT, and white adipose tissue were studied. Corticosterone treatment resulted in a 3.8-fold increase of plasma TG concentrations. Increased TG was normalized by cold exposure, an effect still present 24 hours after cold exposure. Corticosterone treatment increased hepatic TG content by 3.5-fold and provoked secretion of large, TG-rich very low density lipoprotein particles. Cold exposure reduced very low density lipoprotein-TG secretion by approximately 50%. Corticosterone strongly decreased BAT activity: BAT weight increased by 3.5-fold, whereas uncoupling protein 1 (Ucp1) mRNA expression and Ucp1 protein content of BAT were reduced by 75% and 60%, respectively. Cold exposure partially normalized these parameters of BAT activity. The uptake of TG by BAT was not affected by corticosterone treatment but was increased 4.5-fold upon cold exposure. In conclusion, cold exposure normalizes corticosterone-induced hypertriglyceridemia, at least partly via activating BAT.
BackgroundIn mammals, white adipose tissue (WAT) stores fat and brown adipose tissue (BAT) dissipates fat to produce heat. Several studies showed that females have more active BAT. Members of the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families are expressed in BAT and are involved in BAT activity. We hypothesized that differential expression of BMPs and FGFs might contribute to sex differences in BAT activity.MethodsWe investigated the expression of BMPs and FGFs in BAT of male and female C57BL/6J mice upon gonadectomy, cold exposure, and exposure to sex steroids.ResultsOf the FGF family, BAT Fgf1, Fgf9, Fgf18, and Fgf21 expression was induced upon cold exposure, but only Fgf1 expression was obviously different between the sexes: females had 2.5-fold lower BAT Fgf1 than males. Cold exposure induced BAT Bmp4 and Bmp8b expression, but only Bmp8b differed between the sexes: females had 35-fold higher BAT Bmp8b than males. Ovariectomy almost completely blunted BAT Bmp8b expression, while orchidectomy had no effect. Male mice and ovariectomized female mice treated with diethylstilbestrol (DES) had approximately 350-fold and approximately 36-fold higher BAT Bmp8b expression, respectively. Ninety-day and 7-day treatment of female mice with dihydrotestosterone (DHT) decreased BAT Bmp8b expression by approximately fivefold and approximately fourfold, respectively. Finally, treatment of primary murine brown adipocytes with DES did not result in changes in Bmp8b expression.ConclusionsBAT Bmp8b expression in mice is positively regulated by presence of ovaries and estrogens such as DES.
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