Novel 5α‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer
Open accessAbstract
Prostate cancer often relapses during androgen-depletion therapy, even under conditions in which a drastic reduction of circulating androgens is observed. There is some evidence that androgens remain present in the tissues of hormone-refractory prostate cancers (HRPC), and enzymes involved in the androgen and steroid metabolic pathway are likely to be active in HRPC cells. We previously carried out a genome-wide gene expression profile analysis of clinical HRPC cells by means of cDNA microarrays in combination with microdissection of cancer cells and found dozens of transactivated genes. Among them, we here report the identification of a novel gene, SRD5A2L, encoding a putative 5 alpha-steroid reductase that produces the most potent androgen, 5 alpha-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5 alpha-steroid reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5 alpha-steroid reductase. Because two types of 5 alpha-steroid reductase were previously reported, we termed this novel 5 alpha-steroid reductase 'type 3 5 alpha-steroid reductase' (SRD5A3). Reverse transcription-polymerase chain reaction and northern blot analyses confirmed its overexpression in HRPC cells, and indicated no or little expression in normal adult organs. Knockdown of SRD5A3 expression by small interfering RNA in prostate cancer cells resulted in a significant decrease in DHT production and a drastic reduction in cell viability. These findings indicate that a novel type 3 5 alpha-steroid reductase, SRD5A3, is associated with DHT production and maintenance of androgen-androgen receptor-pathway activation in HRPC cells, and that this enzymatic activity should be a promising molecular target for prostate cancer therapy.
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SRD5A3 plays an important role in N-linked protein glycosylation.
“has been shown to play an important role in N-linked protein glycosylation [[96], [97], [98]]”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [96]
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- Authors
- Uemura, M., Tamura, K., Chung, S., Honma, S., Okuyama, A., Nakamura, Y., & Nakagawa, H.
- Affiliations
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Nakagawa, Hidewaki
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2007-11-06
- Volume
- 99
- Issue
- 1
- Pages
- 81-86
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC11158902
- OpenAlex
- W2029877275
- Cited by
- 263
- References
- 29
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 13 · 2023: 11 · 2022: 12 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 14 · 2016: 16 · 2015: 12 · 2014: 18 · 2013: 21 · 2012: 21
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- SRD5A3, castration-resistant prostate cancer, dihydrotestosterone, androgen production, androgen receptor signaling, gene overexpression, siRNA knockdown
- MeSH terms
- Animals, Chlorocebus aethiops, Humans, Male, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Dihydrotestosterone, Testosterone, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Transfection, COS Cells, RNA, Small Interfering, Cell Line, Tumor, Cell Growth Processes
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