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Steroid hormone synthetic pathways in prostate cancer.

Mostaghel EA - Transl Androl Urol (2013)

Bottom Line: The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease.These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy.Finally, we discuss the emerging data regarding mechanisms of response and resistance to potent ligand synthesis inhibitors entering clinical practice, and conclude by discussing the implications of these findings for future therapy.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle WA, USA.

ABSTRACT
While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa) since the seminal recognition of the disease as androgen-dependent by Huggins and Hodges in 1941, therapy is uniformly marked by progression to castration-resistant prostate cancer (CRPC) over a period of about 18 months, with an ensuing median survival of 1 to 2 years. Importantly, castration does not eliminate androgens from the prostate tumor microenvironment. Castration resistant tumors are characterized by elevated tumor androgens that are well within the range capable of activating the AR and AR-mediated gene expression, and by steroid enzyme alterations which may potentiate de novo androgen synthesis or utilization of circulating adrenal androgens. The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease. These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy. Herein, we review the accumulated body of evidence which strongly supports intracrine (tumoral) androgen synthesis as an important mechanism underlying PCa progression. We first discuss the presence and significance of residual prostate tumor androgens in the progression of CRPC. We review the classical and non-classical pathways of androgen metabolism, and how dysregulated expression of these enzymes is likely to potentiate tumor androgen production in the progression to CRPC. Next we review the in vitro and in vivo data in human tumors, xenografts, and cell line models which demonstrate the capacity of prostate tumors to utilize cholesterol and adrenal androgens in the production of testosterone (T) and dihydrotestosterone (DHT), and briefly review the potential role of exogenous influences on this process. Finally, we discuss the emerging data regarding mechanisms of response and resistance to potent ligand synthesis inhibitors entering clinical practice, and conclude by discussing the implications of these findings for future therapy.

No MeSH data available.


Related in: MedlinePlus

Steroid hormone synthesis pathways in the adrenal gland and testis. A. Steroid synthesis in the adrenal gland occurs in three zones, each with a specific complement of enzymes. The zona glomerulosa contains the enzymes necessary to produce aldosterone. The zona fasciculata and reticularis additionally express CYP17A. The hydroxylase activity of CYP17A is active in the zona fasiculata resulting in the production of cortiso. Due to tissue-specific expression of the cytochrome b5 coregulator, the lyase activity of CYP17A is only present in the zona reticularis and drives efficient production of DHEA which is then sulfated to DHEA-S. 17α-OH progesterone is a poor substrate for CYP17A lyase (dotted arrow) and thus androstenedione is formed at lower levels. The zona fasciculate and zona reticularis are sensitive to the ACTH feedback stimulation that occurs when cortisol production is suppressed by inhibition of CYP17A. Agents specifically targeting the lyase but not hydroxylase activity of CYP17A would not inhibit cortisol synthesis and are anticipated to induce less ACTH feedback stimulation; B. Testicular androgen synthesis follows a similar pathway to DHEA formation as that in the zona reticularis. Due to the absence of SULT2A1, and the presence of HSD3B2 and HSD17B3, DHEA is efficiently converted to testosterone.
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f1: Steroid hormone synthesis pathways in the adrenal gland and testis. A. Steroid synthesis in the adrenal gland occurs in three zones, each with a specific complement of enzymes. The zona glomerulosa contains the enzymes necessary to produce aldosterone. The zona fasciculata and reticularis additionally express CYP17A. The hydroxylase activity of CYP17A is active in the zona fasiculata resulting in the production of cortiso. Due to tissue-specific expression of the cytochrome b5 coregulator, the lyase activity of CYP17A is only present in the zona reticularis and drives efficient production of DHEA which is then sulfated to DHEA-S. 17α-OH progesterone is a poor substrate for CYP17A lyase (dotted arrow) and thus androstenedione is formed at lower levels. The zona fasciculate and zona reticularis are sensitive to the ACTH feedback stimulation that occurs when cortisol production is suppressed by inhibition of CYP17A. Agents specifically targeting the lyase but not hydroxylase activity of CYP17A would not inhibit cortisol synthesis and are anticipated to induce less ACTH feedback stimulation; B. Testicular androgen synthesis follows a similar pathway to DHEA formation as that in the zona reticularis. Due to the absence of SULT2A1, and the presence of HSD3B2 and HSD17B3, DHEA is efficiently converted to testosterone.

Mentions: The source of residual androgens within prostate tumors of castrate men has not been fully elucidated, but is generally attributed to the uptake and conversion of circulating adrenal androgens (14,34), and somewhat more controversially, to de novo biosynthesis of androgens from progesterone or cholesterol precursors (35). Here we review the classical pathways of de novo androgen synthesis in adrenal and peripheral tissues [Figure 1, reviewed in (36)], the enzymatic pathways mediating prostate androgen metabolism, and the so called ‘back-door’ pathway of androgen synthesis. A general outline of the classical and non-classical steroidogenic pathways is provided in Figure 2.


Steroid hormone synthetic pathways in prostate cancer.

Mostaghel EA - Transl Androl Urol (2013)

Steroid hormone synthesis pathways in the adrenal gland and testis. A. Steroid synthesis in the adrenal gland occurs in three zones, each with a specific complement of enzymes. The zona glomerulosa contains the enzymes necessary to produce aldosterone. The zona fasciculata and reticularis additionally express CYP17A. The hydroxylase activity of CYP17A is active in the zona fasiculata resulting in the production of cortiso. Due to tissue-specific expression of the cytochrome b5 coregulator, the lyase activity of CYP17A is only present in the zona reticularis and drives efficient production of DHEA which is then sulfated to DHEA-S. 17α-OH progesterone is a poor substrate for CYP17A lyase (dotted arrow) and thus androstenedione is formed at lower levels. The zona fasciculate and zona reticularis are sensitive to the ACTH feedback stimulation that occurs when cortisol production is suppressed by inhibition of CYP17A. Agents specifically targeting the lyase but not hydroxylase activity of CYP17A would not inhibit cortisol synthesis and are anticipated to induce less ACTH feedback stimulation; B. Testicular androgen synthesis follows a similar pathway to DHEA formation as that in the zona reticularis. Due to the absence of SULT2A1, and the presence of HSD3B2 and HSD17B3, DHEA is efficiently converted to testosterone.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4219921&req=5

f1: Steroid hormone synthesis pathways in the adrenal gland and testis. A. Steroid synthesis in the adrenal gland occurs in three zones, each with a specific complement of enzymes. The zona glomerulosa contains the enzymes necessary to produce aldosterone. The zona fasciculata and reticularis additionally express CYP17A. The hydroxylase activity of CYP17A is active in the zona fasiculata resulting in the production of cortiso. Due to tissue-specific expression of the cytochrome b5 coregulator, the lyase activity of CYP17A is only present in the zona reticularis and drives efficient production of DHEA which is then sulfated to DHEA-S. 17α-OH progesterone is a poor substrate for CYP17A lyase (dotted arrow) and thus androstenedione is formed at lower levels. The zona fasciculate and zona reticularis are sensitive to the ACTH feedback stimulation that occurs when cortisol production is suppressed by inhibition of CYP17A. Agents specifically targeting the lyase but not hydroxylase activity of CYP17A would not inhibit cortisol synthesis and are anticipated to induce less ACTH feedback stimulation; B. Testicular androgen synthesis follows a similar pathway to DHEA formation as that in the zona reticularis. Due to the absence of SULT2A1, and the presence of HSD3B2 and HSD17B3, DHEA is efficiently converted to testosterone.
Mentions: The source of residual androgens within prostate tumors of castrate men has not been fully elucidated, but is generally attributed to the uptake and conversion of circulating adrenal androgens (14,34), and somewhat more controversially, to de novo biosynthesis of androgens from progesterone or cholesterol precursors (35). Here we review the classical pathways of de novo androgen synthesis in adrenal and peripheral tissues [Figure 1, reviewed in (36)], the enzymatic pathways mediating prostate androgen metabolism, and the so called ‘back-door’ pathway of androgen synthesis. A general outline of the classical and non-classical steroidogenic pathways is provided in Figure 2.

Bottom Line: The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease.These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy.Finally, we discuss the emerging data regarding mechanisms of response and resistance to potent ligand synthesis inhibitors entering clinical practice, and conclude by discussing the implications of these findings for future therapy.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle WA, USA.

ABSTRACT
While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa) since the seminal recognition of the disease as androgen-dependent by Huggins and Hodges in 1941, therapy is uniformly marked by progression to castration-resistant prostate cancer (CRPC) over a period of about 18 months, with an ensuing median survival of 1 to 2 years. Importantly, castration does not eliminate androgens from the prostate tumor microenvironment. Castration resistant tumors are characterized by elevated tumor androgens that are well within the range capable of activating the AR and AR-mediated gene expression, and by steroid enzyme alterations which may potentiate de novo androgen synthesis or utilization of circulating adrenal androgens. The dependence of CRPC on intratumoral androgen metabolism has been modeled in vitro and in vivo, and residual intratumoral androgens are implicated in nearly every mechanism by which AR-mediated signaling promotes castration-resistant disease. These observations suggest that tissue based alterations in steroid metabolism contribute to the development of CRPC and underscore these metabolic pathways as critical targets of therapy. Herein, we review the accumulated body of evidence which strongly supports intracrine (tumoral) androgen synthesis as an important mechanism underlying PCa progression. We first discuss the presence and significance of residual prostate tumor androgens in the progression of CRPC. We review the classical and non-classical pathways of androgen metabolism, and how dysregulated expression of these enzymes is likely to potentiate tumor androgen production in the progression to CRPC. Next we review the in vitro and in vivo data in human tumors, xenografts, and cell line models which demonstrate the capacity of prostate tumors to utilize cholesterol and adrenal androgens in the production of testosterone (T) and dihydrotestosterone (DHT), and briefly review the potential role of exogenous influences on this process. Finally, we discuss the emerging data regarding mechanisms of response and resistance to potent ligand synthesis inhibitors entering clinical practice, and conclude by discussing the implications of these findings for future therapy.

No MeSH data available.


Related in: MedlinePlus