Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer
Open accessAbstract
In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.
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Alternate 5α-androstanedione pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which SRD5A1 is upregulated and SRD5A2 is downregulated.
“This so called “alternate 5α-androstanedione” pathway is favored in tissues with predominant SRD5A1 expression and in conditions such as castration-resistant prostate cancer in which the expression of SRD5A1 is upregulated and that of SRD5A2 is downregulated [55,58].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [58]
The conversion of A4 to DHT proceeds via the 5α-reduction of A4 to 5α-androstanedione, followed by the conversion of 5α-dione to DHT.
“Indeed, the conversion of A4 (Δ4, 17-keto) to DHT (5α, 17β) proceeds via the 5α-reduction of A4 to 5α-androstanedione (5α-dione, 5α-androstane-3,17-dione), followed by the conversion of 5α-dione to DHT (Chang et al., 2011' Luu-The and Labrie, 2010, Samson et al., 2010) (Fig. 6).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Chang et al., 2011
The 5α-dione pathway is an essential pathway for intratumoral DHT production from adrenal androgen precursors in CRPC when circulating levels of T are significantly reduced by physical or chemical castration.
“It has especially been shown to be an essential pathway for intratumoral DHT production from adrenal androgen precursors in CRPC when circulating levels of T are significantly reduced by physical or chemical castration (Chang et al., 2011, Sharifi and Auchus, 2012).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Chang et al., 2011
Flux through the alternate 5α-dione pathway is due to the preference of SRD5A1, the dominant isoform expressed in CRPC, for A4 over T, coupled to the poor efficiency by which AKR1C3 converts A4 to T.
“The flux through this pathway is due to the preference of SRD5A1, the dominant isoform expressed in CRPC, for A4 over T, coupled to the poor efficiency by which AKR1C3 converts A4 to T (Chang et al., 2011, Sharifi, 2012).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Chang et al., 2011
Cites
Abiraterone and Increased Survival in Metastatic Prostate Cancer
de Bono, J. S., Logothetis, C. J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K. N., Jones, R. J., Goodman, O. B., Saad, F., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1014618 · Cited by 4,407 · cited 1× · see citing works
“The requirement for the intratumoral generation of androgen ligand is exemplified by frequent and often sustained responses toAR antagonists (7, 8), as well as an unprecedented prolongation of survival in chemotherapy-refractory metastatic CRPC conferred by abiraterone acetate, a potent inhibitor of CYP17A1, which is…”
BackgroundThe Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458 · cited 1× · see citing works
“In the setting of CRPC and the absence of gonadal T, dehydroepiandrosterone (DHEA) and its sulfate, the chief adrenal 19-carbon steroid in circulation (12), undergoes conversion to Δ(4)-androstenedione (AD) in prostate cancer (Fig.”
BackgroundSelf-citationMontgomery, R. B., Mostaghel, E. A., Vessella, R., Hess, D. L., Kalhorn, T. F., Higano, C. S., True, L. D., & Nelson, P. S. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0249 · Cited by 1,419 · see citing works
Steroid 5α-reductase: two genes/two enzymes
Russell, D. W., & Wilson, J. D. (1994) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.63.070194.000325 · Cited by 1,105 · see citing works
Androgen Deprivation Therapy for Prostate Cancer
Sharifi, N. (2005) · JAMA · doi:10.1001/jama.294.2.238 · Cited by 1,087 · see citing works
Self-citationStanbrough, M., Bubley, G. J., Ross, K., Golub, T. R., Rubin, M. A., Penning, T. M., Febbo, P. G., & Balk, S. P. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4000 · Cited by 1,082 · see citing works
Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study
Scher, H. I., Beer, T. M., Higano, C. S., Anand, A., Taplin, M., Efstathiou, E., Rathkopf, D. E., Shelkey, J., Yu, E. Y., Alumkal, J. J., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60172-9 · Cited by 1,063 · see citing works
Scher, H. I., & Sawyers, C. L. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.03.4777 · Cited by 1,025 · see citing works
Locke, J. A., Guns, E. S., Lubik, A. A., Adomat, H. H., Hendy, S. C., Wood, C. A., Ettinger, S. L., Gleave, M. E., & Nelson, C. C. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5997 · Cited by 747 · see citing works
Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism
Andersson, S., Berman, D. M., Jenkins, E. P., & Russell, D. W. (1991) · Nature · doi:10.1038/354159a0 · Cited by 643 · see citing works
Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 –isomerase gene family
Simard, J., Ricketts, M.-L., Gingras, S., Soucy, P., Feltus, F. A., & Melner, M. H. (2005) · Endocrine Reviews · doi:10.1210/er.2002-0050 · Cited by 620 · see citing works
Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer
Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B., & Mohler, J. L. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0525 · Cited by 488 · see citing works
Clark, R. V., Hermann, D. J., Cunningham, G. R., Wilson, T. H., Morrill, B. B., & Hobbs, S. F. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030330 · Cited by 467 · see citing works
The intranuclear binding of testosterone and 5α-androstan-17β-ol-3-one by rat prostate
Bruchovsky, N., & Wilson, J. D. (1968) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)94513-8 · Cited by 404 · see citing works
Patrawala, L., Calhoun‐Davis, T., Schneider‐Broussard, R., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0490 · Cited by 347 · see citing works
McConnell, J. D., Wilson, J. D., George, F. W., Geller, J., Pappas, F., & Stoner, E. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.74.3.1371291 · Cited by 325 · see citing works
Deslypère, J. P., Young, M., Wilson, J. D., & McPhaul, M. J. (1992) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(92)90004-p · Cited by 232 · see citing works
LORENCE, M. C., MURRY, B. A., TRANT, J. M., & MASON, J. I. (1990) · Endocrinology · doi:10.1210/endo-126-5-2493 · Cited by 212 · see citing works
Steroid 5α-Reductase Isozymes I and II in Recurrent Prostate Cancer
Titus, M. A., Gregory, C. W., Ford, O. H., Schell, M. J., Maygarden, S. J., & Mohler, J. L. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0738 · Cited by 174 · see citing works
Androgen biosynthetic pathways in the human prostate
Luu-The, V., Bélanger, A., & Labrie, F. (2008) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2008.01.008 · Cited by 169 · see citing works
Thigpen, A. E., Cala, K. M., & Russell, D. W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85349-8 · Cited by 152 · see citing works
DHT Concentrations in Human Prostate Cancer Tissue*
Geller, J., ALBERT, J. D., Loza, D., Geller, S., Stoeltzing, W., & DANIEL, D. L. V. (1978) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-46-3-440 · Cited by 128 · see citing works
Evaul, K., Li, R., Papari-Zareei, M., Auchus, R. J., & Sharifi, N. (2010) · Endocrinology · doi:10.1210/en.2010-0138 · Cited by 81 · see citing works
Self-citationBenefits of Combination Therapy with Flutamide in Patients Relapsing after Castration
Labrie, F., Dupont, A., Giguère, M., Borsanyi, J.-P., Lacourcière, Y., Monfette, G., Emond, J., & Bergeron, N. (1988) · British Journal of Urology · doi:10.1111/j.1464-410x.1988.tb13971.x · Cited by 69 · see citing works
17β-Hydroxysteroid dehydrogenase 3 deficiency
Andersson, S., Russell, D. W., & Wilson, J. D. (1996) · Trends in Endocrinology and Metabolism · doi:10.1016/1043-2760(96)00034-3 · Cited by 63 · see citing works
Rostow, W. W. (1979) · Palgrave Macmillan UK eBooks · doi:10.1007/978-1-349-04353-8 · Cited by 60 · see citing works
Pre-receptor regulation of the androgen receptor
Penning, T. M., Jin, Y., Rižner, T. L., & Bauman, D. R. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.10.008 · Cited by 58 · see citing works
Phase II Study of Dutasteride for Recurrent Prostate Cancer During Androgen Deprivation Therapy
Shah, S. K., Trump, D. L., Sartor, O. A., Tan, W., Wilding, G. E., & Mohler, J. L. (2008) · The Journal of Urology · doi:10.1016/j.juro.2008.10.014 · Cited by 54 · see citing works
Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study
Kibel, A. S. (2011) · Yearbook of Urology · doi:10.1016/j.yuro.2011.05.029 · Cited by 48 · see citing works
Sharifi, N., McPhaul, M. J., & Auchus, R. J. (2010) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e3181ff6bb8 · Cited by 36 · see citing works
Self-citationSharifi, N., McPhaul, M. J., & Auchus, R. J. (2010) · PubMed · Cited by 32 · see citing works
Self-citationGuarna, A., Occhiato, E. G., Machetti, F., et al. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm970297k · Cited by 20 · see citing works
Assessment of steroidogenic pathways that do not require testosterone as intermediate
Luu-The, V. (2011) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci.2011.007 · Cited by 17 · see citing works
Efstathiou, E., Tu, S., Aparicio, A. M., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.15_suppl.4547 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer
Watson, P. A., Arora, V. K., & Sawyers, C. L. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4016 · Cited by 1,536 · see citing works
Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
“expression of SRD5A1 is upregulated and that of SRD5A2 is downregulated [55,58].”
A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer
Chang, K.-H., Li, R., Kuri, B., Lotan, Y., Roehrborn, C. G., Liu, J., Vessella, R., Nelson, P. S., Kapur, P., Guo, X., et al. (2013) · Cell · doi:10.1016/j.cell.2013.07.029 · Cited by 312 · see citing works
Self-citation11-Oxygenated androgens in health and disease
Turcu, A. F., Rege, J., Auchus, R. J., & Rainey, W. E. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0336-x · Cited by 217 · see citing works
Self-citationIntracrine androgen biosynthesis, metabolism and action revisited
Schiffer, L., Arlt, W., & Storbeck, K.-H. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.08.016 · Cited by 217 · see citing works
“, 1995), which is followed by the conversion of 5a-dione to DHT by reduction of the 17-ketone (Chang et al., 2011; Luu-The and Labrie, 2010; Samson et al., 2010).”
InfluentialStorbeck, K.-H., Bloem, L. M., Africander, D., Schloms, L., Swart, P., & Swart, A. C. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.07.006 · Cited by 198 · see citing works
Structural and functional biology of aldo-keto reductase steroid transforming enzymes
Penning, T. M., Wangtrakuldee, P., & Auchus, R. J. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00089 · Cited by 164 · see citing works
Self-citationPretorius, E., Africander, D. J., Vlok, M., Perkins, M. S., Quanson, J., & Storbeck, K.-H. (2016) · PLOS ONE · doi:10.1371/journal.pone.0159867 · Cited by 148 · see citing works
Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer
Bakht, M. K., & Beltran, H. (2025) · Nature Reviews Urology · doi:10.1038/s41585-024-00900-z · Cited by 158 · see citing works
A new dawn for androgens: novel lessons from 11-oxygenated C19 steroids
Pretorius, E., Arlt, W., & Storbeck, K.-H. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.08.014 · Cited by 142 · see citing works
AKR1C3 as a target in castrate resistant prostate cancer
Adeniji, A. O., Chen, M., & Penning, T. M. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.05.012 · Cited by 143 · see citing works
Swart, A. C., Schloms, L., Storbeck, K.-H., Bloem, L. M., Toit, T. D., Quanson, J. L., Rainey, W. E., & Swart, P. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.04.010 · Cited by 125 · see citing works
Steroid biosynthesis and prostate cancer
Sharifi, N., & Auchus, R. J. (2012) · Steroids · doi:10.1016/j.steroids.2012.03.015 · Cited by 116 · see citing works
Self-citationPenning, T. M. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.07.002 · Cited by 117 · see citing works
Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer
Ferraldeschi, R., Sharifi, N., Auchus, R. J., & Attard, G. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0931 · Cited by 93 · see citing works
Self-citationThe metabolism, analysis, and targeting of steroid hormones in breast and prostate cancer
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Clinical significance of 11-oxygenated androgens
Turcu, A. F., & Auchus, R. J. (2017) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000334 · Cited by 80 · see citing works
Self-citationMarti, N., Galván, J. A., Pandey, A. V., Trippel, M., Tapia, C., Müller, M., Perren, A., & Flück, C. E. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.07.029 · Cited by 76 · see citing works
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Swart, A. C., & Storbeck, K.-H. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.12.009 · Cited by 68 · see citing works
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The clinical and biochemical significance of 11-oxygenated androgens in human health and disease
Storbeck, K.-H., & O’Reilly, M. W. (2023) · European Journal of Endocrinology · doi:10.1093/ejendo/lvad047 · Cited by 63 · see citing works
Byrns, M. C., Mindnich, R., Duan, L., & Penning, T. M. (2012) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2011.12.012 · Cited by 60 · see citing works
The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer
Sharifi, N. (2012) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e31823874a4 · Cited by 52 · see citing works
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du Toit, T., & Swart, A. C. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.09.026 · Cited by 34 · see citing works
- Authors
- Chang, K.-H., Li, R., Papari-Zareei, M., Watumull, L., Zhao, Y. D., Auchus, R. J., & Sharifi, N.
- Affiliations
- Division of Hematology and Oncology,
- Division of Endocrinology and Metabolism, Department of Internal Medicine,
- Department of Radiology, and
- Karolinska Institutet (SE)
- Corresponding author
- Sharifi, Nima
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-07-27
- Volume
- 108
- Issue
- 33
- Pages
- 13728-13733
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3158152
- OpenAlex
- W2151317340
- Semantic Scholar
- df18e57cc2f1bdeab8f67fdf354b0db4db0ff7b1
- Cited by
- 346
- References
- 34
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 7 · 2023: 20 · 2022: 15 · 2021: 20 · 2020: 14 · 2019: 20 · 2018: 25 · 2017: 30 · 2016: 27 · 2015: 29 · 2014: 37 · 2013: 42 · 2012: 26
- FWCI
- 31.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Prostate Cancer Foundation (PC080193)
- Medical Research and Materiel Command
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- castration-resistant prostate cancer, SRD5A2, androstenedione, 5α-reduction, androgen production, androgen deprivation therapy resistance, tumor metastases, xenograft models
- MeSH terms
- Animals, Castration, Humans, Male, Membrane Proteins, Prostatic Neoplasms, Dihydrotestosterone, Testosterone, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Transplantation, Heterologous, Disease Progression, Mice, Metabolic Networks and Pathways
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