Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications - PubMed (original) (raw)

Review

Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications

Elahe A Mostaghel et al. Best Pract Res Clin Endocrinol Metab. 2008 Apr.

Abstract

Residual tissue androgens are consistently detected within the prostate tumors of castrate individuals and are thought to play a critical role in facilitating the androgen receptor-mediated signaling pathways leading to disease progression. The source of residual tumor androgens is attributed in part to the uptake and conversion of circulating adrenal androgens. Whether the de novo biosynthesis of androgens from cholesterol or earlier precursors occurs within prostatic tumors is not known, but it has significant implications for treatment strategies targeting sources of androgens exogenous to the prostate versus 'intracrine' sources within the prostatic tumor. Moreover, increased expression of androgen-metabolizing genes within castration-resistant metastases suggests that up-regulated activity of endogenous steroidogenic pathways may contribute to the outgrowth of 'castration-adapted' tumors. These observations suggest that a multi-targeted treatment approach designed to simultaneously ablate testicular, adrenal and intracrine contributions to the tumor androgen signaling axis will be required to achieve optimal therapeutic efficacy.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT, Dr Nelson has served as an advisor to GlaxoSmithKline and Solvay Pharmaceuticals, and has received research funding from GlaxoSmithKline.

Figures

Figure 1

The classical and back-door pathways of androgen biosynthesis. In the classical pathway (solid gray arrow), C21 precursors (pregnenolone and progesterone) are converted to the C19 adrenal androgens dihydroepiandrosterone (DHEA) and androstenedione (AED) by the sequential hydroxylase and lyase activities of CYP17A1. Circulating adrenal androgens (including the sulfated form of DHEA, DHEA-S), enter the prostate and can be converted to testosterone by a series of reactions involving the activity of HSD3B, HSD17B and AKR1C enzymes. Testosterone is then converted to the potent androgen DHT by the activity of SRD5A. In the back-door pathway to DHT synthesis (short gray arrows), C21 precursors are first acted upon by SRD5A and the reductive 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C family members, followed by conversion to C19 androgens via the lyase activity of CYP17A, and subsequently to dihydrotestosterone (DHT) by the action of HSD17B3 and an oxidative 3α-HSD enzyme.

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Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications - PubMed (original) (raw)