Δ⁵-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells

Abstract

It is known that androst-5-ene-3␤,17␤-diol (Adiol), a precursor of testosterone (T), can activate estrogen target genes. The androgenic activity of Adiol itself, however, is poorly understood. Using a transient transfection assay, we here demonstrate in human prostate cancer cells that Adiol can activate androgen receptor (AR) target genes in the presence of AR, and that AR coactivator ARA70 can further enhance this Adiol-induced AR transcriptional activity. In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydroepiandrosterone, does not activate AR target gene in the absence or presence of ARA70. Thin layer chromatography analysis reveals that T, dihydrotestosterone, and 17␤-estradiol are undetectable in human prostate cancer DU145 cells after treatment with Adiol. Additionally, a proteolysis assay shows that a distinct ligand-receptor conformational difference exists between T-AR and Adiol-AR. Together, the above findings and the fact that T, but not Adiol, can induce transcriptional activity in a mutant AR (mtAR708), suggest that, without being metabolized into T, Adiol itself may represent a natural hormone with androgenic activity in human prostate cancer cells. Because two potent antiandrogens, hydroxyf lutamide (Eulexin), and bicalutamide (casodex), that are widely used for the treatment of prostate cancer, fail to block Adiol-mediated induction of AR transcriptional activity in prostate cancer cells, the effectiveness of so-called ''total androgen blockage,'' a standard treatment for prostate cancer, may need to be reevaluated.Androst-5-ene-3␤,17␤-diol (⌬ 5

Antiandrogens fail to block androstenedione‐mediated mutated androgen receptor transactivation in human prostate cancer cells

“…Recently, we demonstrated that another adrenal androgen and precursor of T, D 5 -androstenediol, possesses intrinsic androgenic activity and that both of the antiandrogens fail to block D 5 -androstenediol-induced AR transcriptional activity in prostate cancer cell lines. 12 Although, in the present study, it is possible that D 4 -dione could convert into T in PC-3 or LNCaP cells and thereby induce CAT activity, the blockage of D 4 -dione action might improve androgen ablation therapy. Furthermore, these results will enhance our understanding and may lead to changes in the treatment of prostate cancer. )…”

Identification of steroid derivatives that function as potent antiandrogens

“…9 We then found that ADEK has anti-Adiol effect on AR transcription in prostate cancer cells. 16 In our study, we also measured MMTV-Luc activity to determine whether HAD and OAK inhibit Adiol-induced AR transcription.…”

“…6,9,11,16,17 PSA-Luc containing a natural 6.0 kb promoter and a synthetic (ARE)4-Luc containing 4 copies of androgen response element (ARE) were kindly provided by Dr. A. Mizokami (Kanazawa University, Kanazawa, Japan) and Dr. M.L. Lu (Harvard Medical School, Boston, MA), respectively.…”

“…6c, lanes 1 vs. 7). HAD (1 lM; p 5 0.0560) and OAK (0.1 lM; p < 0.05), as well as ADEK (1 lM; p < 0.05) and HF (1 lM; p < 0.05), showing no significant growth induction in the absence of androgens (lanes 1 vs. 2-6), suppress DHT-stimulated cell growth (lanes 7 vs. [8][9][10][11][12]. Similarly, in PC-3(AR)9 cells, DHT increases the growth by approximately 20% (Fig.…”

“…9,10 We have found that ''adrenal androgens'', precursors of T, including Adiol and Adione, possess intrinsic androgenic activity that was not blocked by hydroxyflutamide (HF) and BC in prostate cancer cells. 9,11 Because castration, with or without antiandrogen, reduces the serum concentration of adrenal androgens by only 40-50%, 12,13 our findings 9,11 suggested a reason for the failure of therapy to prevent AR-positive prostate cancer growth during the androgen-independent state.…”