The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Motohide Uemura - One of the best experts on this subject based on the ideXlab platform.
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5αDH-DOC (5α-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer
Cancer Science, 2010Co-Authors: Motohide Uemura, Suyoun Chung, Seijiro Honma, Ryo Takata, Mutsuo Furihata, Kazuo Nishimura, Norio Nonomura, Yasutomo Nasu, Tsuneharu Miki, Taro ShuinAbstract:Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5α-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and Steroid metabolism, such as 5α-Steroid Reductases, are activated in CRPCs. In this report, we screened eight natural 5αDH-Steroids to search for novel products of 5α-Steroid Reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5α-Steroid Reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5α-dihydro-deoxycorticosterone (5αDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5α-Steroid Reductase (SRD5A1) could convert from DOC to 5αDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5αDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5αDH-DOC and other products of 5α-Steroid Reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration. (Cancer Sci 2010)
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novel 5α Steroid Reductase srd5a3 type 3 is overexpressed in hormone refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)
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Novel 5α‐Steroid Reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)
Hidewaki Nakagawa - One of the best experts on this subject based on the ideXlab platform.
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novel 5α Steroid Reductase srd5a3 type 3 is overexpressed in hormone refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)
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Novel 5α‐Steroid Reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)
N. Skordis - One of the best experts on this subject based on the ideXlab platform.
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5α-Reductase 2 Gene Mutations in Three Unrelated Patients of Greek Cypriot Origin: Identification of an Ancestral Founder Effect
Journal of Pediatric Endocrinology and Metabolism, 2020Co-Authors: N. Skordis, Charles Sultan, Philippos C. Patsalis, Ioanna Bacopoulou, Carolina Sismani, Serge LumbrosoAbstract:INTRODUCTION: 5alpha-Steroid Reductase deficiency (5alphaSRD) is an autosomal recessive enzymatic deficiency. Mutations in the 5alpha-Steroid Reductase type 2 gene (SRD5A2) result in male pseudohermaphroditism caused by decreased dihydrotestosterone (DHT) synthesis--a key hormone of virilization of male external genitalia. AIM: To study for the first time patients from the Greek Cypriot population, describe their clinical characteristics, and identify the genetic mutations of the SRD5A2 gene. PATIENTS AND METHODS: Three unrelated patients with 46,XY karyotype born with ambiguous genitalia were examined. Patient 1 was raised as a girl and was diagnosed with partial androgen insensitivity syndrome, based on the clinical picture and incomplete laboratory investigation at the age of 4 years, and underwent gonadectomy. For this patient sequencing analysis of all five exons of the SRD5A2 gene and exons 2 to 8 of the androgen receptor (AR) gene was performed. Patients 2 and 3 were also born with ambiguous genitalia. The hCG test for these two patients was informative of 5alphaSRD, as it showed elevated T/DHT ratio after stimulation. Despite genetic counseling, both families decided to raise their infants as females because of severe under-virilization. Sequencing of the SRD5A2 gene was also completed for both patients. RESULTS: No mutations were found in the AR sequence for patient 1. Patients 1 and 3 were found homozygous for the mutation A/G at splice junction intron 1/exon 2 and patient 2 was found heterozygous for the same A/G substitution and also heterozygous for an additional mutation, Pro181Leu, in exon 3. CONCLUSIONS: The same mutation in the SRD5A2 gene was identified in three unrelated patients, in both homozygous and heterozygous form. This splice mutation was previously reported in Turkish patients. This underlying genetic abnormality may be characteristic for the Eastern Mediterranean region and is likely due to an ancestor effect.
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Overview of genetic defects in endocrinopathies in the island of Cyprus; evidence of a founder effect.
Genetic Testing and Molecular Biomarkers, 2012Co-Authors: Christos Shammas, Vassos Neocleous, Meropi Toumba, Constantina Costi, Alexia A.p. Phedonos, Elisavet Efstathiou, Andreas Kyriakou, Leonidas A. Phylactou, N. SkordisAbstract:Aim: Hereditary endocrinopathies in Cyprus exhibit evidence of a founder effect and display the influence of past migration patterns. The genetic frequency and mutation pattern of a specific disorder of sex development (DSD), which is classified as 46,XX DSD or 46,XY DSD, and the non-classic form of congenital adrenal hyperplasia (NC-CAH) outline a type of genetic drift. Results: Not only the high prevalence of the NC-CAH p.V281L mutation but also the rarity of CAH large lesions present a genetic diversity similar to that observed in the Middle Eastern countries. In addition, both the high frequency of the 5-alpha Steroid Reductase deficiency (5αSRD) IVS1-2A>G mutation and the carrier frequency of the 17-beta hydroxySteroid dehydrogenase 3 (17β-HSD-3) p.R80Q mutation are good examples of a founder effect. p.R80Q can be considered a founder mutation, even though it has been identified in patients of Dutch, Brazilian, and Portuguese origin. This has led to the speculation that it has a Phoenician origin. Ph...
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Late diagnosis of 5alpha Steroid-Reductase deficiency due to IVS12A>G mutation of the SRD5a2 gene in an adolescent girl presented with primary amenorrhea.
Hormones (Greece), 2011Co-Authors: N. Skordis, Christos Shammas, Vassos Neocleous, Elisavet Efstathiou, Amalia Sertedaki, Leonidas A. PhylactouAbstract:BACKGROUND: The clinical spectrum of 5α-Reductase deficiency, caused by mutations in the SRD5A2 gene, ranges from complete female appearance of the external genitalia at birth to nearly complete male phenotype. cAse rePOrt: A 14-year-old girl presented with primary amenorrhea (PA) and lack of breast development. she was 173 cm in height, had an increased amount of pubic hair and clitoromegaly (3 cm), with a 4 cm blind vaginal pouch. Gonads were palpable in the inguinal canal bilaterally and no uterus was identified on ultrasound. chromosomal analysis showed a 46,XY karyotype. t he testosterone/DHt ratio was high (16.5) and further increased to 29.4 after stimulation with hcG, thus favouring the diagnosis of 5α-Reductase deficiency. Since the issue of gender change was not considered, gonadectomy was performed followed by successful feminisation with hormonal replacement therapy. GeNetIc stUDIes: Molecular analysis of the SRD5A2 gene by DNA sequencing of all 5 exons revealed the presence of the splice mutation A>G at position -2 of the acceptor site of intron 1/exon 2 (Ivs1-2A>G) in homozygosity. both non-consanguineous parents were found to be heterozygotes for this mutation. cONcLUsIONs: Although rare, SRD5A2 gene defect should be suspected in any girl presenting with PA and virilisation at puberty. the Ivs1-2A>G mutation of the SRD5A2 gene predominates in Greek-Cypriot patients with 5α-Reductase deficiency and very likely reflects a founder effect.
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Late diagnosis of 5alpha Steroid-Reductase deficiency due to IVS12A>G mutation of the SRD5a2 gene in an adolescent girl presented with primary amenorrhea
Hormones, 2011Co-Authors: N. Skordis, Christos Shammas, Vassos Neocleous, Elisavet Efstathiou, Amalia Sertedaki, Leonidas PhylactouAbstract:BACKGROUND The clinical spectrum of 5α-Reductase deficiency, caused by mutations in the SRD5A2 gene, ranges from complete female appearance of the external genitalia at birth to nearly complete male phenotype. CASE REPORT A 14-year-old girl presented with primary amenorrhea (PA) and lack of breast development. She was 173 cm in height, had an increased amount of pubic hair and clitoromegaly (3 cm), with a 4 cm blind vaginal pouch. Gonads were palpable in the inguinal canal bilaterally and no uterus was identified on ultrasound. Chromosomal analysis showed a 46,XY karyotype. The Testosterone/DHT ratio was high (16.5) and further increased to 29.4 after stimulation with hCG, thus favouring the diagnosis of 5α-Reductase deficiency. Since the issue of gender change was not considered, gonadectomy was performed followed by successful feminisation with hormonal replacement therapy. GENETIC STUDIES Molecular analysis of the SRD5A2 gene by DNA sequencing of all 5 exons revealed the presence of the splice mutation A>G at position -2 of the acceptor site of intron 1/exon 2 (IVS1-2A>G) in homozygosity. Both non-consanguineous parents were found to be heterozygotes for this mutation. CONCLUSIONS Although rare, SRD5A2 gene defect should be suspected in any girl presenting with PA and virilisation at puberty. The IVS1-2A>G mutation of the SRD5A2 gene predominates in Greek-Cypriot patients with 5α-Reductase deficiency and very likely reflects a founder effect.
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The IVS1- 2A>G mutation in the SRD5A2 gene predominates in Cypriot patients with 5α Reductase deficiency
Journal of Endocrinological Investigation, 2010Co-Authors: N. Skordis, V. Neocleous, A. Kyriakou, E. Efstathiou, A. Sertedaki, P. Philibert, L. A. Phylactou, S. Lumbroso, C. SultanAbstract:Background : 5α Steroid Reductase deficiency (5αSRD) is an autosomal recessive enzymatic deficiency and mutations in the 5α Steroid Reductase type 2 gene (SRD5A2) result in male pseudohermaphrodism caused by decreased dihydrotestosterone (DHT) synthesis. Aim : To identify the specific mutations of the SRD5A2 gene in Cypriot patients with 5αSRD. Subjects and methods : Five unrelated patients with 46,XY karyotype were examined. Four of them were born with ambiguous genitalia and 1 patient, who was raised as girl, presented with primary amenorrhea. The hCG test was informative (elevated testosterone/DHT) of 5αSRD in 3 out of 4 subjects. Sequencing of the SRD5A2 gene was completed for all patients. Genomic DNA was also isolated from a total of 204 healthy unrelated Cypriot subjects. Screening for the IVS1-2A>G mutation was performed by using direct sequencing and restriction enzyme analysis. Results : The IVS1-2A>G was identified in homozygosity in 3 patients and in a compound heterozygote state in the other 2 patients, in combination with p.P181L and p.R171S in exon 3, respectively. The carrier frequency in the Cypriot population for the IVS1-2A>G mutation was estimated to be 0.98% or 2 in 204. Conclusions : The same IVS1-2A>G mutation in the SRD5A2 gene seems to characterize all Cypriot patients with 5αSRD diagnosed so far. Furthermore this relatively rare genetic defect, which has only been reported previously in a single case in the Eastern Mediterranean region, is very likely to be the result of a founder effect.
Gönül Öcal - One of the best experts on this subject based on the ideXlab platform.
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Mutations of the 5alpha-Steroid Reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village.
Journal of Pediatric Endocrinology and Metabolism, 2020Co-Authors: Gönül Öcal, Pelin Adiyaman, Ergun Cetinkaya, Nejat Akar, Ali Uysal, T. Duman, Zehra Aycan, Merih Berberoğlu, Evliyaoğlu O, Serge LumbrosoAbstract:Abstract We describe six Turkish patients with 5alpha-Steroid Reductase type 2 deficiency from unrelated Turkish families and a large pedigree of one of these patients who reside north-west of Anatolia. Patients NA, KS, BD and SY presented for evaluation of bilateral inguinal masses with female phenotypes. Patient ABE had penoscrotal hypospadias with male phenotype. Homozygous mutation of the 5alphaSR2 gene was identified in five of these patients by genomic DNA analysis. These mutations were Leu55Gln in exon 1 (in patients FG, BD and ABE), deltaMet157 in exon 3 (in patient NA), and splice junction abnormality in intron 1 (in patient SY). One individual (patient KS) was found to be a compound heterozygous carrier of two different mutations, Leu55Gln in exon 1 and Arg171Ser in exon 3. Patient FG had a large pedigree with the Leu55Gln mutation in exon 1. The pedigree of this family with marital consanguinity is remarkable, and possibly due to the isolation of this family because of economic and social problems. A further 85 individuals belonging to this family were analyzed for exon 1 Leu55Gln mutations in the 5alphaSR2 gene. Forty-two of these 85 individuals (49.41%) had this alteration; 11 were homozygous (8 genetic male, 3 genetic female) and 31 heterozygous (18 genetic male, genetic female) for this mutation. It was interesting to see asymptomatic homozygous female carriers. In conclusion, according to our results and those of other Turkish patients reported by different investigators, 5aSR2 gene mutation analysis, especially for Leu55Gln in exon 1 and deltaMet157 in exon 3, must be carried out in Turkish patients with male pseudohermaphroditism. Homozygous asymptomatic female carriers must be taken into consideration in this clinical entity, especially in a closed population, because of the risk of transmitting the disease to their offspring.
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A novel mutation of 5α-Steroid Reductase 2 deficiency (CD 65 ALA-PRO) with severe virilization defect in a Turkish family and difficulty in gender assignment
European Journal of Pediatrics, 2010Co-Authors: Senay Savas Erdeve, Nejat Akar, Zehra Aycan, Merih Berberoğlu, Zeynep Siklar, Bulent Hacıhamdıoglu, Kadir Sıpahı, Gönül ÖcalAbstract:Molecular genetic characterization of mutations in SRD5 A2 gene is used as an essential procedure for the final diagnosis of 5α-Reductase deficiency. Here, we report a novel homozygous point mutation of SRD5A2 gene at codon 65 in exon 1, due to a proline for alanine substitution in a Turkish family whose proband has severe undervirilization. This mutation has not been reported up to date in association with 5α-Reductase deficiency in various ethnic groups. We discussed some questions about gender assignment in addition to the molecular and clinical characteristics of the disease.
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5 alpha Steroid Reductase deficiency in Turkey.
Pediatric endocrinology reviews, 2006Co-Authors: Pelin Adiyaman, Gönül Öcal, Ergun Cetinkaya, Nejat Akar, Ali Uysal, T. Duman, Olcay Evliyaoğlu, Zehra Aycan, Serge Lumbroso, Charles SultanAbstract:: 5 alpha Steroid Reductase 2 (5 alpha SR2) deficiency is an autosomal recessive enzyme defect causing male pseudohermaphroditism (MPH) because of an abnormally low peripheral conversion of testosterone to dihydrotestosterone (DHT), which is required for the normal differentiation of external male genitalia. The present report describes the distribution of 5 alpha Steroid Reductase gene mutations in the Turkish population in the light of published reports from different centers. Eight Turkish patients from unrelated Turkish families and a large pedigree of one of these patients are also discussed. These patients were followed up at Ankara University Department of Pediatric Endocrinology. The presence of Leu 55 Gln mutation in six patients out of 8 indicates the increased prevalence of this mutation in the Turkish population with different presentations. One patient out of six (patient FG) had a large pedigree of Leu 55 Gln mutation in exon 1. The pedigree of this family with marital consanguinity was very remarkable and extraordinary. A further 85 members of this family were analyzed for exon 1 Leu 55 Gln 5 alpha SR2 gene mutations. Forty two out of the 85 subjects (49.41% ) had this alteration in gene mutation. Thirty-one of them were heterozygous (18 genetic male, 13 genetic female) and 11 of them were homozygous (8 genetic male, 3 asymptomatic female carriers) for this mutation. A trinucleotid deletion at straddling codons 156 and 157 is responsible for a methionize residue at position 157 (delta Met 157) of 5 alpha SR type 2 gene which was first described in our patient NA. Two additional Turkish patients were reported by different investigators with this rare mutation and this also suggests an increased prevalence of this mutation in the Turkish population. In conclusion Leu 55 Gln mutation in exon 1 seems to be a hot spot in Turkish patients. Hence 5 alpha SR2 gene mutation analysis especially Leu 55 Gln mutation in exon 1 and delta Met 157 in exon 3, must be evaluated in Turkish patients with male pseudohermaphroditism according to our results and other Turkish patients reported by different investigators. It is important that homozygous asymptomatic female carriers be taken into consideration in this clinical entity especially in closed populations because of the risk of carrying the disease to their offspring.
Suyoun Chung - One of the best experts on this subject based on the ideXlab platform.
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5αDH-DOC (5α-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer
Cancer Science, 2010Co-Authors: Motohide Uemura, Suyoun Chung, Seijiro Honma, Ryo Takata, Mutsuo Furihata, Kazuo Nishimura, Norio Nonomura, Yasutomo Nasu, Tsuneharu Miki, Taro ShuinAbstract:Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5α-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and Steroid metabolism, such as 5α-Steroid Reductases, are activated in CRPCs. In this report, we screened eight natural 5αDH-Steroids to search for novel products of 5α-Steroid Reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5α-Steroid Reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5α-dihydro-deoxycorticosterone (5αDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5α-Steroid Reductase (SRD5A1) could convert from DOC to 5αDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5αDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5αDH-DOC and other products of 5α-Steroid Reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration. (Cancer Sci 2010)
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novel 5α Steroid Reductase srd5a3 type 3 is overexpressed in hormone refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)
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Novel 5α‐Steroid Reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer
Cancer Science, 2007Co-Authors: Motohide Uemura, Kenji Tamura, Suyoun Chung, Seijiro Honma, Akihiko Okuyama, Yusuke Nakamura, Hidewaki NakagawaAbstract: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 5α-Steroid Reductase that produces the most potent androgen, 5α-dihydrotestosterone (DHT), from testosterone. Liquid chromatography-tandem mass spectrometry analysis following an in vitro 5α-Steroid Reductase reaction validated its ability to produce DHT from testosterone, similar to type 1 5α-Steroid Reductase. Because two types of 5α-Steroid Reductase were previously reported, we termed this novel 5α-Steroid Reductase ‘type 3 5α-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 5α-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. (Cancer Sci 2008; 99: 81–86)