5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores

Opoku-Acheampong, Alexander B.; Henningson, Jamie; Beck, Amanda P.; Lindshield, Brian L.

doi:10.1371/journal.pone.0175874

Cited by 4 publications

(7 citation statements)

References 33 publications

(50 reference statements)

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“…Previous research has reported that SRD5A1 is highly expressed in prostate cancer (PC) ( 15 , 19 , 20 ), breast cancer ( 21 , 22 ), non-small cell lung cancer ( 23 ), and liver cancer ( 24 ). The upregulation of SRD5A1 promotes the formation and development of prostate intraepithelial neoplasia in vivo ( 25 ). Dutasteride, an inhibitor of SRD5A1/2 ( 26 ), which prevents T to DHT conversion, performs key functions in PC cell viability and proliferation ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is a common malignant tumor of the digestive system. Steroid 5α-reductase type I (SRD5A1), as an important part of the steroid metabolism, converts testosterone to dihydrotestosterone and regulates sex hormone levels, which accommodates tumor occurrence or development. However, the underlying molecular mechanism of SRD5A1 in CRC remains unclear. We compared SRD5A1 expression in CRC tissues with normal controls by immunohistochemistry and found that elevated SRD5A1 in CRC was relevant for poor patient prognosis. Furthermore, inducible downregulation of SRD5A1 by small hairpin RNA reduced cell viability, promoted cell cycle arrest, and induced cell apoptosis and cellular senescence of CRC cells, as well as attenuated cell migration ability. In the following experiments, we used dutasteride (an inhibitor of SRD5A1/2) to explore its inhibitory effect on the biological processes of CRC cells, as mentioned earlier. Further mechanism study demonstrated that the repression of SRD5A1 abolished the expression of p65 and vascular endothelial growth factor, suggesting that SRD5A1 might regulate cell viability and migration through nuclear factor-κB/vascular endothelial growth factor signaling pathway. Collectively, these findings implicate SRD5A1 acting as a novel biomarker for CRC diagnosis and prognosis and provide compelling evidence for the future evaluation of dutasteride as a promising candidate for CRC treatment.

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Section: Introductionmentioning

confidence: 99%

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer

et al. 2020

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“…Even though 5α-reductase 1 has been found to increase in high grade versus low grade prostate cancer [ 54 , 55 ], this study is the first to report that tumor 5α-reductase 1 levels are positively correlated with adjusted prostate lesion score severity. Previously we found that prostate epithelium 5α-reductase 1 levels were positively correlated with adjusted prostate lesion score severity [30] . Collectively these may suggest that elevated 5α-reductase 1 levels are a characteristic of the increased malignant potential of tumors with higher prostate lesion scores.…”

Section: Discussionmentioning

confidence: 83%

“…The expression levels of Ki-67 and AR protein, apoptotic DNA fragmentation were quantified using IHC; and 5α-reductase 1 and 5α-reductase 2 mRNA were quantified using ISH in formalin-fixed, paraffin-embedded prostate tissue sections of AIN–93 G control, Pre-Finasteride, Post-Finasteride, Pre-Dutasteride, and Post-Dutasteride (n = 5) treated male TRAMP mice with GU weight < 1 gram; and AIN–93 G control, Pre-Finasteride, Post-Finasteride (n = 4), Pre-Dutasteride (n = 2), and Post-Dutasteride (n = 4) treated male TRAMP mice with GU weight > 1 gram. Biomarker assays and quantification in prostate epithelium, hyperplasia and tumor were performed as described previously [30] . Thresholds for positivity were defined so that they matched what was seen visually.…”

Section: Methodsmentioning

confidence: 99%

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The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates

Opoku-Acheampong

Henningson

Lindshield

2017

Heliyon

Self Cite

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BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/Principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

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“…The major sites of distribution of SRD5A in the human tissues are both in the reproductive organs (where the isoform SRD5A2 is prevalent) and in non-reproductive tissues, such as liver and skin, in which isoform SRD5A1 is the most commonly present [18,30]. In experimental animal models, it has been observed that the up-regulation of SRD5A1 promotes the formation and development of rat prostate intraepithelial neoplasia in vivo [31].…”

Section: Sex Steroid Hormones (Androgens)mentioning

confidence: 99%

Endocrine Disruptors and Prostate Cancer

Corti

Lorenzetti

Ubaldi

et al. 2022

IJMS

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The role of endocrine disruptors (EDs) in the human prostate gland is an overlooked issue even though the prostate is essential for male fertility. From experimental models, it is known that EDs can influence several molecular mechanisms involved in prostate homeostasis and diseases, including prostate cancer (PCa), one of the most common cancers in the male, whose onset and progression is characterized by the deregulation of several cellular pathways including androgen receptor (AR) signaling. The prostate gland essentiality relies on its function to produce and secrete the prostatic fluid, a component of the seminal fluid, needed to keep alive and functional sperms upon ejaculation. In physiological condition, in the prostate epithelium the more-active androgen, the 5α-dihydrotestosterone (DHT), formed from testosterone (T) by the 5α-reductase enzyme (SRD5A), binds to AR and, upon homodimerization and nuclear translocation, recognizes the promoter of target genes modulating them. In pathological conditions, AR mutations and/or less specific AR binding by ligands modulate differently targeted genes leading to an altered regulation of cell proliferation and triggering PCa onset and development. EDs acting on the AR-dependent signaling within the prostate gland can contribute to the PCa onset and to exacerbating its development.

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5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores

Cited by 4 publications

References 33 publications

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer

The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates

Endocrine Disruptors and Prostate Cancer

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