Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer. 2013

Fumio Ishizaki, and Tsutomu Nishiyama, and Takashi Kawasaki, and Yoshimichi Miyashiro, and Noboru Hara, and Itsuhiro Takizawa, and Makoto Naito, and Kota Takahashi
Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), a key enzyme of oxidative 3α-HSD that catalyzes the conversion of 3α-diol to DHT in prostate cancer cells. Correspondingly, the score for HSD17B6 in tissues of 42 prostate cancer patients undergoing androgen deprivation therapy (ADT) was about 2-fold higher than that in tissues of 100 untreated individuals. In men receiving ADT, patients showing biochemical progression had a higher HSD17B6 score than those without progression. These results suggested that 3α/β-diol also represent potential precursors of DHT, and the back conversion of DHT from androgen derivatives can be a promising target for combination hormone therapy.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D011471 Prostatic Neoplasms Tumors or cancer of the PROSTATE. Cancer of Prostate,Prostate Cancer,Cancer of the Prostate,Neoplasms, Prostate,Neoplasms, Prostatic,Prostate Neoplasms,Prostatic Cancer,Cancer, Prostate,Cancer, Prostatic,Cancers, Prostate,Cancers, Prostatic,Neoplasm, Prostate,Neoplasm, Prostatic,Prostate Cancers,Prostate Neoplasm,Prostatic Cancers,Prostatic Neoplasm
D003687 Dehydroepiandrosterone A major C19 steroid produced by the ADRENAL CORTEX. It is also produced in small quantities in the TESTIS and the OVARY. Dehydroepiandrosterone (DHEA) can be converted to TESTOSTERONE; ANDROSTENEDIONE; ESTRADIOL; and ESTRONE. Most of DHEA is sulfated (DEHYDROEPIANDROSTERONE SULFATE) before secretion. Dehydroisoandrosterone,Prasterone,5-Androsten-3-beta-hydroxy-17-one,5-Androsten-3-ol-17-one,Androstenolone,DHEA,Prasterone, 3 alpha-Isomer,5 Androsten 3 beta hydroxy 17 one,5 Androsten 3 ol 17 one,Prasterone, 3 alpha Isomer
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000368 Aged A person 65 years of age or older. For a person older than 79 years, AGED, 80 AND OVER is available. Elderly
D000728 Androgens Compounds that interact with ANDROGEN RECEPTORS in target tissues to bring about the effects similar to those of TESTOSTERONE. Depending on the target tissues, androgenic effects can be on SEX DIFFERENTIATION; male reproductive organs, SPERMATOGENESIS; secondary male SEX CHARACTERISTICS; LIBIDO; development of muscle mass, strength, and power. Androgen,Androgen Receptor Agonist,Androgen Effect,Androgen Effects,Androgen Receptor Agonists,Androgenic Agents,Androgenic Compounds,Agents, Androgenic,Agonist, Androgen Receptor,Agonists, Androgen Receptor,Compounds, Androgenic,Effect, Androgen,Effects, Androgen,Receptor Agonist, Androgen,Receptor Agonists, Androgen
D013196 Dihydrotestosterone A potent androgenic metabolite of TESTOSTERONE. It is produced by the action of the enzyme 3-OXO-5-ALPHA-STEROID 4-DEHYDROGENASE. 5 alpha-Dihydrotestosterone,Androstanolone,Stanolone,17 beta-Hydroxy-5 beta-Androstan-3-One,17beta-Hydroxy-5alpha-Androstan-3-One,5 beta-Dihydrotestosterone,5-alpha Dihydrotestosterone,5-alpha-DHT,Anaprotin,Andractim,Dihydroepitestosterone,Gelovit,17 beta Hydroxy 5 beta Androstan 3 One,17beta Hydroxy 5alpha Androstan 3 One,5 alpha DHT,5 alpha Dihydrotestosterone,5 beta Dihydrotestosterone,Dihydrotestosterone, 5-alpha,beta-Hydroxy-5 beta-Androstan-3-One, 17
D015067 17-Hydroxysteroid Dehydrogenases A class of enzymes that catalyzes the oxidation of 17-hydroxysteroids to 17-ketosteroids. EC 1.1.-. 17 beta-Hydroxysteroid Dehydrogenases,Testosterone Dehydrogenases,17-Ketosteroid Reductases,17 Hydroxysteroid Dehydrogenases,17 Ketosteroid Reductases,17 beta Hydroxysteroid Dehydrogenases,Dehydrogenases, 17 beta-Hydroxysteroid,Dehydrogenases, 17-Hydroxysteroid,Dehydrogenases, Testosterone,Reductases, 17-Ketosteroid
D015113 Androstane-3,17-diol The unspecified form of the steroid, normally a major metabolite of TESTOSTERONE with androgenic activity. It has been implicated as a regulator of gonadotropin secretion. 5 Androstane 3,17 diol,5 alpha-Androstane-3 alpha,17 beta-diol,5 alpha-Androstane-3 beta,17 alpha-diol,5 alpha-Androstane-3 beta,17 beta-diol,5 alpha-Androstane-3alpha,17 beta-diol,5 beta-Androstane-3 alpha,17 beta-diol,5-Androstane-3,17-diol,5alpha-Androstane-3beta,17alpha-diol,5 alpha Androstane 3 alpha,17 beta diol,5 alpha Androstane 3 beta,17 alpha diol,5 alpha Androstane 3 beta,17 beta diol,5 alpha Androstane 3alpha,17 beta diol,5 beta Androstane 3 alpha,17 beta diol,5alpha Androstane 3beta,17alpha diol,Androstane 3,17 diol

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