Impaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor Signaling

Abstract

We previously reported the selective loss of AKR1C2 and AKR1C1 in prostate cancers compared with their expression in paired benign tissues. We now report that dihydrotestosterone (DHT) levels are significantly greater in prostate cancer tumors compared with their paired benign tissues. Decreased catabolism seems to account for the increased DHT levels as expression of AKR1C2 and SRD5A2 was reduced in these tumors compared with their paired benign tissues. After 4 h of incubation with benign tissue samples, 3 H-DHT was predominately catabolized to the 5A-androstane-3A,17B-diol metabolite. Reduced capacity to metabolize DHT was observed in tumor samples from four of five freshly isolated pairs of tissue samples, which paralleled loss of AKR1C2 and AKR1C1 expression. LAPC-4 cells transiently transfected with AKR1C1 and AKR1C2, but not AKR1C3, were able to significantly inhibit a dose-dependent, DHT-stimulated proliferation, which was associated with a significant reduction in the concentration of DHT remaining in the media. R1881-stimulated proliferation was equivalent in all transfected cells, showing that metabolism of DHT was responsible for the inhibition of proliferation. PC-3 cells overexpressing AKR1C2 and, to a lesser extent, AKR1C1 were able to significantly inhibit DHT-dependent androgen receptor reporter activity, which was abrogated by increasing DHT levels. We speculate that selective loss of AKR1C2 in prostate cancer promotes clonal expansion of tumor cells by enhancement of androgen-dependent cellular proliferation by reducing DHT metabolism. [Cancer Res 2007;67(3):1361-9]

The Effect of Allelic Variation in Aldo-Keto Reductase 1C2 on the in Vitro Metabolism of Dihydrotestosterone

“…With these caveats, we propose that the apparent kinetic properties we have measured will be useful for comparative studies that will help elucidate the role of AKR1C2 in vivo. Previous studies have performed comparisons of differences in AKR1C2 expression in prostate cancer and benign prostate tissues (Ji et al, 2003(Ji et al, , 2007. These investigators demonstrated that the cancerous tissues had higher levels of DHT accompanied by lower expression of AKR1C2.…”

“…Thus, AKR1C2 has a pivotal role in modulating DHT levels and, consequently, in regulating receptor signaling in androgen-dependent tissues such as the prostate (Ji et al, 2007;Penning et al, 2008). Furthermore, recent evidence suggests that 3␣-diol has important pharmacological roles that do not involve the androgen receptor.…”

AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects

“…Similarly, others have identified AKR1C3 as a possible target in prostate and breast carcinoma (11,12). Equally, other studies have identified AKR1C2 and AKR1C1 as potential targets for the treatment of prostate, breast, lung, and bladder carcinomas (12)(13)(14)(15). Thus, the availability of AKR1C-selective inhibitors would be of value in the chemoprevention of cancers, in use as adjuvant therapies in combination with established chemotherapeutics and as direct therapeutic interventions in their own right.…”

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

“…Higher serum testosterone to DHT ratios have been associated with increased risk of prostate cancer in some studies [25][26][27]. But in primary prostate cancer cells DHT levels have been reported to be higher in tumor than adjacent normal cells [38]. If the HSD3B2 (TG)n,(TA)n,(CA)n polymorphism does have an impact on gene expression, the resulting impact on testosterone and DHT levels may or may not be equivalent.…”