Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy

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   Figure 1

   Outline of steps mediating androgen synthesis and metabolism in prostate cancer cells. Pathways that may contribute to androgen synthesis in prostate are outlined. Bold arrows and brackets outline what appears to be the major pathway for generation of testosterone and DHT in PCa cells after ADT when adrenal synthesis of weak androgens is intact and there are high levels of circulating DHEA-S. PCa cells can also synthesize at least trace amounts of testosterone directly from cholesterol through the sequential actions of CYP11A1, CYP17A1, HSD3B1 or 2, and AKR1C3 through the pathway that is normally active only in the adrenal glands and testes (also shown in brackets). It should be noted that testes uses 17β-hydroxysteroid dehydrogenase type 3 rather than AKR1C3 to generate testosterone (not shown). A possible alternative ‘backdoor’ pathway is also shown that may bypass testosterone and generate DHT from androsterone. In some cases more than one enzyme can carry out a particular step (HSD3B1 or HSD3B2; AKR1C2 or AKR1C3; and SRD5A1 or SRD5A2). Inhibitors of enzymes in the pathways are also indicated.

• © 2011 Society for Endocrinology