Thursday, October 3, 2013
Figure 1. Androgen synthesis pathways in prostate cancer. In testicular androgen
synthesis, luteinizing hormone-releasing hormone (LHRH) stimulates release of
luteinizing hormone (LH) from the pituitary gland, which signals the testes to
secrete testosterone [a(1)]. Testosterone enters the prostate cancer
cell and is converted to the potent androgen dihydrotestosterone (DHT) by 5-a reductase (5aR) [d]. DHT
binds and activates the androgen receptor (AR)
[e], which in turn initiates transcription of oncogenic genes increasing
proliferation and survival [f].
In castration-resistant androgen synthesis, the pituitary
gland also signals the adrenal gland to initiate an adrenocorticotropic hormone
(ACTH)-mediated androgen synthesis pathway [a(2)]. The switch from
dependence on the testicular to the adrenal androgen synthesis pathway can
occur following surgical or chemical castration, leading to tumor regrowth.
Through a series of reactions catalyzed by cytochrome P450 17 a-hydroxylase/17, 20
lyase (CYP17), cholesterol is
converted into dehydroepiandrosterone (DHEA) [b(2)].The CYP17 inhibitor
abiraterone blocks the production of DHEA and downstream androgen synthesis in
the adrenal androgen synthesis pathway. However, it may incompletely inhibit
this step and lead to resistance. Hydroxysteroid 3b
dehydrogenase 1 (HSD3B1), the gene
that encodes 3bHSD1, catalyzes the rate-limiting step in the pathway
that converts DHEA to testosterone, which is then converted to DHT to activate
AR [c(2)]. DHEA may also be converted to DHT independently of
testosterone through a 3bHSD1-dependent pathway [c(3)].
A gain-of-stabilization mutation in HSD3B1 can increase the flux from
DHEA to DHT, possibly allowing sufficient production of DHT from the residual
androgen precursors remaining during abiraterone treatment leading to
therapeutic resistance. Inhibitors of 3bHDS1 may prevent this resistance pathway.