Androgen Action in Prostate Cancer

Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro

“…Despite these efforts, resistance continues to emerge and one mechanism which we and others have demonstrated to be important is intratumoral de novo steroidogenesis [2]. Although castration levels of androgens are found in serum, high levels of testosterone and DHT were found in resistant tumor samples resulting in the AR reactivation [6]. Enzymes responsible for de novo steroidogenesis, including cytochrome P450 11A1 (CYP11A1), cytochrome P450 17A1 (CYP17A1), SRD5A1, 17-beta-hydroxysteroid dehydrogenase type 3 (HSD17B3), 3-beta-hydroxysteroid dehydrogenase/delta 5!4-isomerase type 2 (HSD3B2), aldo-keto reductase family C3 (AKR1C3) and steroidogenic acute regulatory protein (STAR) are among the proteins found to be upregulated in primary and metastatic tumors thus facilitating the local synthesis of testosterone and DHT from cholesterol [2,[7][8][9].…”

“…DHT, a 10-fold more potent AR ligand than testosterone, activates the AR and triggers cell proliferation and survival signals [3]. Androgen ablation therapy in conjunction with AR inhibitors are used to inhibit testosterone production and AR activation which ultimately arrests tumor proliferation [4,5]. Despite these efforts, resistance continues to emerge and one mechanism which we and others have demonstrated to be important is intratumoral de novo steroidogenesis [2].…”

“…The 22RV1 cells also contain many AR splice variants which present another resistance mechanism for survival [28]. Dehydroepiandrosterone (DHEA) is produced and secreted by the adrenal glands and progesterone appears to be upregulated in tumor xenografts [2,6]. Both substrates are important in the castrate environment as potential precursors for androgen biosynthesis.…”