AKR1C3（5 型 17β-羟甾脱氢酶/前列腺素 F 合酶）：在恶性肿瘤和内分泌紊乱中的作用。
AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders.
机构信息
Department of Systems Pharmacology and Translational Therapeutics and Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 1315 BRBII/III 421 Curie Blvd, Philadelphia, PA, 19104, USA.
出版信息
Mol Cell Endocrinol. 2019 Jun 1;489:82-91. doi: 10.1016/j.mce.2018.07.002. Epub 2018 Sep 19.
Abstract
Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F synthase) is the only 17β-HSD that is not a short-chain dehydrogenase/reductase. By acting as a 17-ketosteroid reductase, AKR1C3 produces potent androgens in peripheral tissues which activate the androgen receptor (AR) or act as substrates for aromatase. AKR1C3 is implicated in the production of androgens in castration-resistant prostate cancer (CRPC) and polycystic ovarian syndrome; and is implicated in the production of aromatase substrates in breast cancer. By acting as an 11-ketoprostaglandin reductase, AKR1C3 generates 11β-PGF to activate the FP receptor and deprives peroxisome proliferator activator receptorγ of its putative PGJ ligands. These growth stimulatory signals implicate AKR1C3 in non-hormonal dependent malignancies e.g. acute myeloid leukemia (AML). AKR1C3 moonlights by acting as a co-activator of the AR and stabilizes ubiquitin ligases. AKR1C3 inhibitors have been used clinically for CRPC and AML and can be used to probe its pluripotency.
摘要
醛酮还原酶 1C3（类型 5 17β-羟甾类脱氢酶（HSD）/前列腺素（PG）F 合酶）是唯一不是短链脱氢酶/还原酶的 17β-HSD。AKR1C3 作为 17-酮甾体还原酶，在周围组织中产生有效的雄激素，这些雄激素激活雄激素受体（AR）或作为芳香酶的底物。AKR1C3 参与去势抵抗性前列腺癌（CRPC）和多囊卵巢综合征中的雄激素产生；并参与乳腺癌中芳香酶底物的产生。AKR1C3 作为 11-酮前列腺素还原酶，生成 11β-PGF 以激活 FP 受体并剥夺过氧化物酶体增殖物激活受体γ的潜在 PGJ 配体。这些生长刺激信号暗示 AKR1C3 参与非激素依赖性恶性肿瘤，例如急性髓细胞性白血病（AML）。AKR1C3 兼职作为 AR 的共激活剂，并稳定泛素连接酶。AKR1C3 抑制剂已在临床上用于 CRPC 和 AML，可用于探索其多能性。
相似文献
1
AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders.AKR1C3（5 型 17β-羟甾脱氢酶/前列腺素 F 合酶）：在恶性肿瘤和内分泌紊乱中的作用。
Mol Cell Endocrinol. 2019 Jun 1;489:82-91. doi: 10.1016/j.mce.2018.07.002. Epub 2018 Sep 19.
2
Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.醛酮还原酶（AKR）1C3抑制剂：专利综述
Expert Opin Ther Pat. 2017 Dec;27(12):1329-1340. doi: 10.1080/13543776.2017.1379503. Epub 2017 Sep 19.
3
11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer.11-氧代雄激素前体是醛酮还原酶 1C3（AKR1C3）的首选底物：对去势抵抗性前列腺癌的影响。
J Steroid Biochem Mol Biol. 2018 Oct;183:192-201. doi: 10.1016/j.jsbmb.2018.06.013. Epub 2018 Jun 21.
4
Human dehydrogenase/reductase SDR family member 11 (DHRS11) and aldo-keto reductase 1C isoforms in comparison: Substrate and reaction specificity in the reduction of 11-keto-C-steroids.人源脱氢酶/还原酶短链家族成员 11（DHRS11）和醛酮还原酶 1C 同工酶的比较：在 11-酮-C-甾体还原反应中的底物和反应特异性。
J Steroid Biochem Mol Biol. 2020 May;199:105586. doi: 10.1016/j.jsbmb.2020.105586. Epub 2020 Jan 8.
5
Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer.在 MCF-7 细胞中醛酮还原酶 1C3 的表达揭示了其在甾体激素和前列腺素代谢中的作用，这可能解释了其在乳腺癌中的过度表达。
J Steroid Biochem Mol Biol. 2010 Feb 15;118(3):177-87. doi: 10.1016/j.jsbmb.2009.12.009. Epub 2009 Dec 28.
6
Characterization of the major single nucleotide polymorphic variants of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase).醛酮还原酶 1C3（类型 5 17β-羟类固醇脱氢酶）的主要单核苷酸多态性变异的特征。
J Steroid Biochem Mol Biol. 2022 Jul;221:106121. doi: 10.1016/j.jsbmb.2022.106121. Epub 2022 Apr 28.
7
A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics.一种 3-(4-硝基萘-1-基)氨基苯甲酸酯类似物作为双功能 AKR1C3 抑制剂和 AR 拮抗剂：与其他先进的 AKR1C3 靶向治疗药物的头对头比较。
J Steroid Biochem Mol Biol. 2019 Sep;192:105283. doi: 10.1016/j.jsbmb.2019.01.001. Epub 2019 Jan 11.
8
Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs.5型17β-羟基类固醇脱氢酶/前列腺素F合酶（AKR1C3）：在乳腺癌中的作用及非甾体抗炎药类似物对其的抑制作用
Chem Biol Interact. 2009 Mar 16;178(1-3):221-7. doi: 10.1016/j.cbi.2008.10.024. Epub 2008 Nov 1.
9
Differential expression of type 2 3α/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in tumors of the central nervous system.2型3α/5型17β-羟基类固醇脱氢酶（AKR1C3）在中枢神经系统肿瘤中的差异表达。
Int J Clin Exp Pathol. 2010 Mar 25;3(8):743-54.
10
An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies.一种消炎痛类似物，N-(4-氯苯甲酰基)-褪黑素，是醛糖酮还原酶1C3（2型3α-羟基类固醇脱氢酶、5型17β-羟基类固醇脱氢酶和前列腺素F合酶）的选择性抑制剂，醛糖酮还原酶1C3是治疗激素依赖性和非激素依赖性恶性肿瘤的潜在靶点。
Biochem Pharmacol. 2008 Jan 15;75(2):484-93. doi: 10.1016/j.bcp.2007.09.008. Epub 2007 Sep 14.
引用本文的文献
1
Aldo-keto reductase family 1 member C3 (AKR1C3) gene polymorphism (rs12529) is associated with breast cancer in Bangladeshi population: A case-control study and computational investigation.醛酮还原酶家族1成员C3（AKR1C3）基因多态性（rs12529）与孟加拉人群乳腺癌的相关性：一项病例对照研究及计算分析。
PLoS One. 2025 Jun 9;20(6):e0318079. doi: 10.1371/journal.pone.0318079. eCollection 2025.
2
Steroids Static Postural Balance Changes After Exercise Intervention Correlate with Steroidome in Elderly Female.运动干预后老年女性类固醇与静态姿势平衡变化的相关性研究
Metabolites. 2025 Apr 1;15(4):239. doi: 10.3390/metabo15040239.
3
A case of familial partial lipodystrophy type 2 masquerading as Cushing syndrome: Explaining an atypical phenotype by whole-exome sequencing.一例伪装成库欣综合征的2型家族性部分脂肪营养不良：通过全外显子组测序解释非典型表型
Arch Endocrinol Metab. 2025 Mar 24;69(1):e240293. doi: 10.20945/2359-4292-2024-0293.
4
AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis through the Nrf-2/NF-κB pathway.醛酮还原酶1C3通过Nrf-2/NF-κB信号通路保护心肌细胞免受缺氧诱导的细胞凋亡。
Acta Biochim Biophys Sin (Shanghai). 2025 Mar 6;57(7):1151-1163. doi: 10.3724/abbs.2024230.
5
Identification and validation of five ferroptosis-related molecular signatures in keloids based on multiple transcriptome data analysis.基于多转录组数据分析的瘢痕疙瘩中五个铁死亡相关分子特征的鉴定与验证
Front Mol Biosci. 2025 Jan 6;11:1490745. doi: 10.3389/fmolb.2024.1490745. eCollection 2024.
6
Advances in ferroptosis for castration-resistant prostate cancer treatment: novel drug targets and combination therapy strategies.铁死亡在去势抵抗性前列腺癌治疗中的进展：新型药物靶点与联合治疗策略
Prostate Cancer Prostatic Dis. 2024 Dec 28. doi: 10.1038/s41391-024-00933-w.
7
AKR1C3 mediates gastric cancer cell invasion and metastasis via the AKT and JNK/p-NF-κB signaling pathways.醛酮还原酶1C3通过AKT和JNK/p-核因子κB信号通路介导胃癌细胞的侵袭和转移。
Sci Rep. 2024 Dec 4;14(1):30263. doi: 10.1038/s41598-024-82039-w.
8
Reversible downregulation of MYC in a spheroid model of metastatic epithelial ovarian cancer.转移性上皮性卵巢癌球体模型中MYC的可逆性下调
Cancer Gene Ther. 2025 Jan;32(1):83-94. doi: 10.1038/s41417-024-00850-z. Epub 2024 Nov 21.
9
The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia.第三代 AKR1C3 激活前药 ACHM-025 根除了侵袭性 T 细胞急性淋巴细胞白血病的临床前模型中的疾病。
Blood Cancer J. 2024 Nov 6;14(1):192. doi: 10.1038/s41408-024-01180-x.
10
Identification of Pyroptosis-Related Molecular Subtypes and Diagnostic Model development in Major Depressive Disorder.重度抑郁症中焦亡相关分子亚型的鉴定及诊断模型的建立
Mol Biotechnol. 2024 Aug 23. doi: 10.1007/s12033-024-01252-0.
本文引用的文献
1
DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.DHX15 通过刺激 Siah2 介导的雄激素受体泛素化促进前列腺癌的进展。
Oncogene. 2018 Feb 1;37(5):638-650. doi: 10.1038/onc.2017.371. Epub 2017 Oct 9.
2
Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.醛酮还原酶（AKR）1C3抑制剂：专利综述
Expert Opin Ther Pat. 2017 Dec;27(12):1329-1340. doi: 10.1080/13543776.2017.1379503. Epub 2017 Sep 19.
3
AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome.AKR1C3介导的脂肪雄激素生成导致多囊卵巢综合征女性的脂毒性。
J Clin Endocrinol Metab. 2017 Sep 1;102(9):3327-3339. doi: 10.1210/jc.2017-00947.
4
Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.抑制AKR1C3激活可克服晚期前列腺癌对阿比特龙的耐药性。
Mol Cancer Ther. 2017 Jan;16(1):35-44. doi: 10.1158/1535-7163.MCT-16-0186. Epub 2016 Oct 28.
5
Quality of life effects of androgen deprivation therapy in a prostate cancer cohort in New Zealand: can we minimize effects using a stratification based on the aldo-keto reductase family 1, member C3 rs12529 gene polymorphism?新西兰前列腺癌队列中雄激素剥夺治疗对生活质量的影响：我们能否基于醛糖还原酶家族1成员C3 rs12529基因多态性进行分层以将影响降至最低？
BMC Urol. 2016 Aug 2;16(1):48. doi: 10.1186/s12894-016-0164-4.
6
Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases.非同义单核苷酸多态性对依西美坦在肝胞质溶胶还原酶作用下体外代谢的影响。
Pharmacogenet Genomics. 2016 Aug;26(8):370-80. doi: 10.1097/FPC.0000000000000226.
7
A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency.17β-羟类固醇脱氢酶5型基因启动子区域的单核苷酸变异影响21-羟化酶缺乏女性的外生殖器男性化。
Horm Res Paediatr. 2016;85(5):333-8. doi: 10.1159/000445684. Epub 2016 Apr 16.
8
Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells.敲低AKR1C3可揭示前列腺癌细胞中潜在的表观遗传易感性。
J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):47-55. doi: 10.1016/j.jsbmb.2015.09.037. Epub 2015 Sep 30.
9
Effect of insulin on AKR1C3 expression in female adipose tissue: in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome.胰岛素对女性脂肪组织中 AKR1C3 表达的影响：多囊卵巢综合征脂肪雄激素生成的体内和体外研究。
Lancet. 2015 Feb 26;385 Suppl 1:S16. doi: 10.1016/S0140-6736(15)60331-2.
10
Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase.醛酮还原酶1B15的底物特异性、抑制剂选择性及结构-功能关系：一种新型人类视黄醛还原酶
PLoS One. 2015 Jul 29;10(7):e0134506. doi: 10.1371/journal.pone.0134506. eCollection 2015.
Zotero 插件