br Introduction br Prostate cancer is the
Prostate cancer is the second most common cancer in human males and is the second leading cause of cancer-related death in American males. Androgen receptor (AR)-mediated gene transcription in the target tissue is critical to the proliferation and progression of PCa (Dai et al., 2017; Stuchbery et al., 2017; Mohler, 2008), with the circulating testicular androgens testosterone (T) and dihydrotestosterone (DHT) as the preferred AR-activating ligands (Wilson and French, 1976). An-drogen deprivation therapy (ADT), whether medical or surgical, is used to reduce the levels of circulating T and DHT, and inhibit AR-mediated gene expression in the target organ, and has represented the standard-of-care for treatment of locally advanced and metastatic PCa for over seventy years. Patients treated with ADT respond well initially, how-ever, the majority of PCas treated with ADT progress to castration-re-sistant prostate cancer (CRPC). CRPC is the lethal form of PCa, and currently there is no eﬀective therapy to treat CRPC.
Mounting evidence indicates that T and DHT production in PCa cells, also called intracrine steroidogenesis, is a/the mechanism for resistance of CRPC to ADT (Dai et al., 2017; Stuchbery et al., 2017). PCa Nocodazole may acquire the ability to utilize cholesterol, androgenic meta-bolites of cholesterol, or precursors to androgenic steroids as substrates for local production of T and/or DHT, and therefore, bypass the re-quirement for circulating T and DHT for maintaining AR activity.
Mechanisms proposed for intra-tumoral intracrine steroidogenesis in-clude: the front-door pathway, which uses DHEA and androstenedione (A4) as precursors to generate T that is further reduced to DHT by 5α-reductase (SRD5A)-1, −2, or −3; the back-door pathway, which is initiated by the SRD5A1 reduction of 17-hydroxyprogesterone to pro-duce DHT through sequential intermediates androstenediol and an-drostanediol and therefore without T as an intermediate (Kamrath et al., 2012a, 2012b); and the second back-door pathway, which also metabolizes progesterone to produce DHT without T as an intermediate but with androstanedione as an intermidiate (Stuchbery et al., 2017; Mohler et al., 2011; Mostaghel, 2013; Fiandalo et al., 2014). Another pathway that converts A4 to produce 11-ketotestosterone (11 KT) and 11-kto-5 < alpha > -dihydrotestosterone (11KD) (Pretorius et al., 2016, 2017; Storbeck et al., 2013) has emerged recently as a potentially important androgen metabolism pathway. In this newly established pathway, A4 is hydroxylated by cytochrome P450 11β-hydroxylase (CYP11B1) to 11β-hydroxyandrostenedione (11OH-A4), which is fur-ther metabolized to 11 KT and 11KDHT. Since 11 KT and 11KDHT were found to be potent AR agonists (Pretorius et al., 2016; Storbeck et al., 2013; Bloem et al., 2015), DHEAS, DHEA and A4 may contribute to the production of AR-stimulatory androgens in addition to T and DHT. The actual implementation of these pathways would depend on the ex-pression of key enzymes in tumor tissue, the presence of the requisite substrates and co-factors, whether production of DHT can bypass T as
∗ Corresponding author. Department of Urology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buﬀalo, NY 14263, USA. E-mail address: [email protected] (Y. Wu).
an intermediate, and the changes in expression of enzymes and in the concentrations of substrates/co-factors in response to the specific type of ADT. Potential proximal precursors for intracrine production of T and DHT in humans and other primates include dehydroepian-drosterone (DHEA) and DHEA-sulfate (DHEAS) that are produced in the adrenal glands (Rainey et al., 2002). DHEAS is the predominant adrenal androgen, and the most abundant androgen in the circulation. Levels of circulating DHEAS and DHEA are in the range of 3.5 μM and 10 nM, respectively (Travis et al., 2007; Wurzel et al., 2007; Ryan et al., 2007). Further, the concentrations of DHEAS and DHEA remain in the μM and nM ranges after ADT (Snaterse et al., 2017). DHEA is metabolized to androstenedione (and further to androstanedione), or to androstene-diol, all of which can be converted in a single step to T or DHT as part of the front door androgen metabolism pathway (Stuchbery et al., 2017; Fiandalo et al., 2014). The adrenal gland also produce other C19 ster-oids in addition to DHEAS, DHEA, and A4, such as 11OH-A4, which is produced in adrenal gland at substantial amount and exists in the serum in nM range (Rege et al., 2013; du Toit et al., 2017). Therefore, the involvement of C19 adrenal steroids in intra-tumoral production of AR-stimulatory androgens are not limited to the more traditional DHEAS and DHEA to T and/or DHT conversion.