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INVITED RESEARCH HIGHLIGHT
Year : 2014  |  Volume : 16  |  Issue : 1  |  Page : 99-100

More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer


Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA

Date of Web Publication16-Dec-2013

Correspondence Address:
Elizabeth M Wilson
Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.122200

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How to cite this article:
Wilson EM. More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer. Asian J Androl 2014;16:99-100

How to cite this URL:
Wilson EM. More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer. Asian J Androl [serial online] 2014 [cited 2019 Oct 17];16:99-100. Available from: http://www.ajandrology.com/text.asp?2014/16/1/99/122200 - DOI: 10.4103/1008-682X.122200

A gain-of-function stabilizing somatic mutation in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1, HSD3B1) was reported in castration-resistant prostate cancer. The A→C nucleotide polymorphism replaced asparagine-367 with threonine (3βHSD1-N367T) as a homozygous somatic mutation in a subset of castration-resistant prostate cancers by loss of heterozygosity of the wild-type allele. Increased stability of 3βHSD1-N367T was associated with decreased ubiquitin-mediated degradation and higher levels of dihydrotestosterone (DHT). The studies suggest that genetic instability in castration-resistant prostate cancer favors the more stable 3βHSD1-N367T mutant that contributes to drug resistance. A somatic mutation in a steroid metabolic enzyme required for DHT synthesis provides further support for intratumoral androgen synthesis contributing to prostate cancer progression.

It has been known for >60 years that growth of prostate cancer depends on testicular androgen. Prostate cancers undergo remission for 1-2 years following androgen deprivation therapy, but recur in the absence of testicular androgen. Recurrence of prostate cancer growth during androgen deprivation therapy by medical castration using luteinizing hormone releasing hormone (LHRH) agonists has been attributed to increased expression of the androgen receptor (AR) and its coregulators, and to intratumoral androgen biosynthesis. [1],[2],[3],[4],[5] Synthesis of DHT, the most potent androgen that activates AR transcriptional activity, depends on a series of metabolic enzymes that catalyze the oxidation and reduction of steroid precursors from the adrenal gland or from cholesterol.

A recent study by Chang et al. [6] provides evidence that a gain-of-function 3bHSD1 somatic mutation contributes to prostate cancer progression by conferring resistance to proteasome-mediated degradation. 3bHSD1, like its other family member 3bHSD2, is an intracellular membrane-bound steroid metabolic enzyme with dual functions: Oxidization of the 3b-hydroxyl to 3-keto of 5α-configured steroids, and isomerization of the ∆5 carbon-carbon double bond to ∆4. 3bHSD1 and 3bHSD2 utilize NAD+ cofactors to catalyze four irreversible oxidative hydroxysteroid reactions in the pathway toward DHT synthesis: Conversion of pregnenolone to progesterone, conversion of 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, conversion of dehydroepiandrosterone (DHEA) to ∆4-androstenedione, and conversion of ∆5-androstenediol to testosterone.

Both 3bHSDs are essential enzymes in the de novo synthesis of DHT. 3bHSD1 contributes to androgen metabolism primarily in peripheral tissues such as prostate, and 3bHSD2 is expressed predominantly in the adrenal gland and testis. One pathway of DHT synthesis that is independent of testosterone synthesis in castration-resistant prostate cancer is the conversion of adrenal-derived DHEA by 3bHSD1 to ∆4-androstenedione, which is converted by 5α-reductase to 5α-androstanedione, and then by 17b-HSD to form DHT. [7] The gain-of-function 3bHSD1-N367T mutant described by Chang et al. extends the half-life of 3bHSD1 and is associated with increased synthesis of DHT from DHEA. The studies suggest that a somatic mutation in a steroid metabolic enzyme contributes to prostate cancer progression.

Rare loss or gain-of-function mutations can significantly impact reproductive function and provide insight into basic mechanisms. Loss-of-function AR germline mutations that cause the androgen insensitivity syndrome and a female external phenotype in affected genetic males demonstrate the requirement for AR in male reproductive system development. Loss-of-function 5α-reductase mutations cause an androgen insensitivity phenotype at birth and demonstrate a requirement for DHT in male reproductive development. Gain-of-function AR somatic mutations in prostate cancer can expand the repertoire of steroids that activate AR. Loss-of-function 3bHSD2 mutations cause incomplete masculinization in the male and a form of congenital adrenal hyperplasia, which in the female fetus can result in partial virilization due to the accumulation of adrenal androgen. The lack of reported loss-of-function 3bHSD1 mutations may reflect the requirement for placental synthesis of progesterone during pregnancy. [8] The 3bHSD1 gain-of-function gene mutation described by Chang et al. provides additional evidence that intratumoral DHT synthesis contributes to the growth of castration-resistant prostate cancer.

In humans, high circulating levels of the adrenal androgen DHEA-sulfate are taken up by prostate cancer cells and converted to DHEA, a substrate for 3bHSD1 in the synthesis of DHT. Metabolism of DHEA, 5α-androstane-3α,17β-diol or other adrenal precursors to testosterone or DHT is required for the activation of wild-type AR. [9] However, rare somatic AR mutations in prostate cancer can introduce structural stability in the ligand-binding domain that facilitates direct activation of the AR mutant by DHEA. [10],[11] Such gain-of-function AR mutations emphasize the importance of AR mediated gene transcription in prostate cancer growth and progression. A role of 3bHSD1 in intratumoral DHT synthesis from adrenal precursors suggested by the gain-of-function mutation described by Chang et al. supports the contribution of intratumoral androgen production to prostate cancer growth during androgen deprivation therapy.

However, an array of therapeutic interventions that target AR or androgen biosynthetic enzymes has thus far met with only limited success in blocking the growth of castration-resistant prostate cancer. AR remains a principal target of moderate affinity antiandrogens that compete with high affinity intratumoral DHT. The effectiveness of antiandrogen therapy in early stage prostate cancer demonstrates the contribution of AR to prostate cancer growth. However, antiandrogen treatment of most cases of late stage castration-resistant prostate cancer extends life by only several months. Even though AR remains a critical target in the growth of advanced prostate cancer, genetic instability inherent to cancer cells enables them to circumvent drug intervention by optimizing AR activation through multiple mechanisms. This includes rare cases of gain-of-function mutations in AR and most recently 3bHSD1.

Intratumoral DHT derived from adrenal precursors, de novo synthesis from cholesterol, or backdoor pathways independent of testosterone synthesis, [9],[12] contributes to AR activation and prostate cancer growth. The multiple metabolic pathways involved in DHT synthesis provide a growing list of potential targets for pharmacological intervention. Abiraterone acetate slows prostate cancer growth through the inhibition of cytochrome P450 17A1 (CYP17A1), an enzyme that converts progesterone precursors to DHT, [13] and by weak inhibition of 3bHSD1. [14] Studies of Chang et al. suggest that loss of response to abiraterone acetate may reflect in part genetic selection of the more stable 3bHSD1-N367T allele, and therefore provide evidence for the contribution of genetic instability to castration-resistant tumor growth. Expression of wild-type or mutant 3bHSD1 is heterogeneous among prostate cancer cell lines and tumors, [6] with low 3bHSD1 protein levels in LAPC-4 cells, low 3bHSD1 mRNA in locally confined prostate cancers, [15] higher 3bHSD1 protein in LNCaP cells, and higher 3bHSD1 mRNA in castration-resistant prostate cancer. [4] Therapy to block 3bHSD1 activity and inhibit the synthesis of DHT from DHEA supports the importance of intratumoral DHT synthesis to prostate cancer growth, and further highlights the complication of genetic adaptability to treatment outcome. A multi-targeted approach to inhibit AR and key steroidogenic enzymes earlier in the course of disease progression may provide the best chance for reduced mortality from prostate cancer.

 
  References Top

1.Geller J, Albert J, Loza D, Geller S, Stoeltzing W, et al. DHT concentrations in human prostate cancer tissue. J Clin Endocrinol Metab 1978; 46: 440-4.  Back to cited text no. 1
[PUBMED]    
2.Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004; 10: 440-8.  Back to cited text no. 2
    
3.Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res 2007; 67: 5033-41.  Back to cited text no. 3
[PUBMED]    
4.Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res 2008; 68: 4447-54.  Back to cited text no. 4
[PUBMED]    
5.Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008; 68: 6407-15.  Back to cited text no. 5
[PUBMED]    
6.Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 2013; 154: 1074-84.  Back to cited text no. 6
[PUBMED]    
7.Evaul K, Li R, Papari-Zareei M, Auchus RJ, Sharifi N. 3beta-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer. Endocrinology 2010; 151: 3514-20.  Back to cited text no. 7
[PUBMED]    
8.Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32: 81-151.  Back to cited text no. 8
[PUBMED]    
9.Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res 2011; 71: 1486-96.  Back to cited text no. 9
[PUBMED]    
10.Tan JA, Sharief Y, Hamil KG, Gregory CW, Zang DY, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 1997; 11: 450-9.  Back to cited text no. 10
    
11.He B, Gampe RT, Hnat AT, Faggart JL, Minges JT, et al. Probing the functional link between androgen receptor coactivator and ligand binding sites in prostate cancer and androgen insensitivity. J Biol Chem 2006; 281: 6648-63.  Back to cited text no. 11
    
12.Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab 2004; 15: 432-8.  Back to cited text no. 12
[PUBMED]    
13.de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995-2005.  Back to cited text no. 13
[PUBMED]    
14.Li R, Evaul K, Sharma KK, Chang KH, Yoshimoto J, et al. Abiraterone inhibits 3b-hydroxysteroid dehydrogenase: A rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res 2012; 18: 3571-9.  Back to cited text no. 14
    
15.Hofland J, van Weerden WM, Dits NF, Steenbergen J, van Leenders GJ, et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res 2010; 70: 1256-64.  Back to cited text no. 15
[PUBMED]    



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