类固醇激素转化醛酮还原酶与癌症
Steroid hormone transforming aldo-keto reductases and cancer.
作者信息
Penning Trevor M, Byrns Michael C
机构信息
Center of Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
出版信息
Ann N Y Acad Sci. 2009 Feb;1155:33-42. doi: 10.1111/j.1749-6632.2009.03700.x.
Abstract
Prostate and breast cancer are hormone-dependent malignancies of the aging male and female and require the local production of androgens and estrogens to stimulate cell proliferation. Aldo-keto reductases (AKR) play key roles in this process. In the prostate, AKR1C3 (type 5 17beta-HSD) reduces Delta(4)-androstene-3,17-dione to yield testosterone while AKR1C2 (type 3 3alpha-HSD) eliminates 5alpha-dihydrotestosterone (5alpha-DHT), and AKR1C1 forms 3beta-androstanediol (a ligand for ERbeta). In the breast, AKR1C3 forms testosterone, which is converted to 17beta-estradiol by aromatase or reduces estrone to 17beta-estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF(2alpha) and 11beta-PGF(2alpha), which stimulate the FP receptor and prevent the activation of PPARgamma by PGJ(2) ligands. This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer.
摘要
前列腺癌和乳腺癌是老年男性和女性的激素依赖性恶性肿瘤，需要局部产生雄激素和雌激素来刺激细胞增殖。醛酮还原酶（AKR）在这一过程中起关键作用。在前列腺中，AKR1C3（5型17β-羟基类固醇脱氢酶）将Δ4-雄烯-3,17-二酮还原生成睾酮，而AKR1C2（3型3α-羟基类固醇脱氢酶）消除5α-二氢睾酮（5α-DHT），AKR1C1形成3β-雄烷二醇（雌激素受体β的一种配体）。在乳腺中，AKR1C3生成睾酮，睾酮可通过芳香化酶转化为17β-雌二醇，或直接将雌酮还原为17β-雌二醇。AKR1C3还作为前列腺素（PG）F合酶，形成PGF2α和11β-PGF(2α)，它们刺激FP受体并阻止PGJ2配体激活过氧化物酶体增殖物激活受体γ（PPARγ）。这种促增殖信号可能刺激激素依赖性和非依赖性前列腺癌和乳腺癌的生长。
相似文献
1
Steroid hormone transforming aldo-keto reductases and cancer.类固醇激素转化醛酮还原酶与癌症
Ann N Y Acad Sci. 2009 Feb;1155:33-42. doi: 10.1111/j.1749-6632.2009.03700.x.
2
Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones.醛酮还原酶超家族的人类3α-羟基类固醇脱氢酶亚型（AKR1C1-AKR1C4）：功能可塑性和组织分布揭示其在雄性和雌性性激素失活与形成中的作用。
Biochem J. 2000 Oct 1;351(Pt 1):67-77. doi: 10.1042/0264-6021:3510067.
3
Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3).5型17β-羟基类固醇脱氢酶（AKR1C3）的结构-功能方面及抑制剂设计
Mol Cell Endocrinol. 2001 Jan 22;171(1-2):137-49. doi: 10.1016/s0303-7207(00)00426-3.
4
Characterization of a monoclonal antibody for human aldo-keto reductase AKR1C3 (type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate.人醛糖酮还原酶AKR1C3（2型3α-羟基类固醇脱氢酶/5型17β-羟基类固醇脱氢酶）单克隆抗体的特性；乳腺和前列腺中的免疫组织化学检测
Steroids. 2004 Dec;69(13-14):795-801. doi: 10.1016/j.steroids.2004.09.014.
5
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.
6
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.
7
Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): overview and structural insights.5 型 17β-羟甾脱氢酶（AKR1C3）抑制剂：概述和结构见解。
J Steroid Biochem Mol Biol. 2011 May;125(1-2):95-104. doi: 10.1016/j.jsbmb.2010.11.004. Epub 2010 Nov 16.
8
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.
9
Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells.人3型3α-羟基类固醇脱氢酶（醛酮还原酶1C2）与前列腺细胞中的雄激素代谢
Endocrinology. 2003 Jul;144(7):2922-32. doi: 10.1210/en.2002-0032.
10
Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a delta5(10)-3-ketosteroid.替勃龙通过醛糖酮还原酶1C亚家族的四种人类同工酶的3α/3β-羟基类固醇脱氢酶活性进行代谢：对δ5(10)-3-酮类固醇的立体特异性进行反转。
Mol Pharmacol. 2004 Dec;66(6):1702-11. doi: 10.1124/mol.104.004515. Epub 2004 Sep 21.
引用本文的文献
1
Per- and Polyfluoroalkyl Substances (PFAS) Enhance Cholesterol Accumulation and Dysregulate Inflammatory Responses in Macrophages.全氟和多氟烷基物质（PFAS）增强巨噬细胞中的胆固醇积累并失调炎症反应。
Cardiovasc Toxicol. 2025 Jul 29. doi: 10.1007/s12012-025-10048-w.
2
Genetic and computational analysis of AKR1C4 gene rs17134592 polymorphism in breast cancer among the Bangladeshi population.孟加拉人群乳腺癌中AKR1C4基因rs17134592多态性的遗传与计算分析
Sci Rep. 2025 Jul 28;15(1):27526. doi: 10.1038/s41598-025-13411-7.
3
BLID is a drug-responsive target of FOXO3a and multi-omics analysis reveals survival mechanisms and therapeutic vulnerabilities in BLID-deficient breast cancer cells.BLID是FOXO3a的药物反应靶点，多组学分析揭示了BLID缺陷型乳腺癌细胞的生存机制和治疗脆弱性。
Oncol Lett. 2025 Jun 24;30(3):409. doi: 10.3892/ol.2025.15155. eCollection 2025 Sep.
4
Analysis of Expression and Regulation of AKR1C2 in HPV-Positive and -Negative Oropharyngeal Squamous Cell Carcinoma.HPV阳性和阴性口咽鳞状细胞癌中AKR1C2的表达及调控分析
Cancers (Basel). 2024 Aug 27;16(17):2976. doi: 10.3390/cancers16172976.
5
Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway.人类AKR1C3与GPR84激动剂结合并参与扩展的多胺途径。
Cell Chem Biol. 2025 Jan 16;32(1):126-144.e18. doi: 10.1016/j.chembiol.2024.07.011. Epub 2024 Aug 19.
6
Aldo-keto reductases: Role in cancer development and theranostics.醛酮还原酶：在癌症发生发展和治疗中的作用。
Oncol Res. 2024 Jul 17;32(8):1287-1308. doi: 10.32604/or.2024.049918. eCollection 2024.
7
Cancer to Cataracts: The Mechanistic Impact of Aldo-Keto Reductases in Chronic Diseases.从癌症到白内障：醛酮还原酶在慢性疾病中的作用机制。
Yale J Biol Med. 2024 Jun 28;97(2):179-204. doi: 10.59249/VTBV6559. eCollection 2024 Jun.
8
AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation.AKR1C4 通过调控铁死亡来调节结直肠癌细胞对化疗的敏感性。
Cancer Chemother Pharmacol. 2024 Sep;94(3):373-385. doi: 10.1007/s00280-024-04685-1. Epub 2024 Jun 18.
9
Defining the biological functions and clinical significance of AKR1C3 in gastric carcinogenesis through multiomics functional analysis and immune infiltration analysis.通过多组学功能分析和免疫浸润分析确定AKR1C3在胃癌发生中的生物学功能和临床意义。
J Cancer. 2024 Mar 17;15(9):2646-2658. doi: 10.7150/jca.94228. eCollection 2024.
10
High-Throughput Transcriptomics of Nontumorigenic Breast Cells Exposed to Environmentally Relevant Chemicals.环境相关化学物质暴露的非致瘤性乳腺细胞的高通量转录组学研究。
Environ Health Perspect. 2024 Apr;132(4):47002. doi: 10.1289/EHP12886. Epub 2024 Apr 3.
本文引用的文献
1
Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.CYP17选择性抑制剂醋酸阿比特龙的I期临床试验证实，去势抵抗性前列腺癌通常仍由激素驱动。
J Clin Oncol. 2008 Oct 1;26(28):4563-71. doi: 10.1200/JCO.2007.15.9749. Epub 2008 Jul 21.
2
Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance.选择性雌激素调节剂作为一种抗癌工具：作用机制及耐药性
Adv Exp Med Biol. 2008;630:206-19. doi: 10.1007/978-0-387-78818-0_13.
3
Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.转移性前列腺癌中瘤内雄激素的维持：去势抵抗性肿瘤生长的一种机制。
Cancer Res. 2008 Jun 1;68(11):4447-54. doi: 10.1158/0008-5472.CAN-08-0249.
4
Suppression of aromatase in human breast cells by a cyclooxygenase-2 inhibitor and its analog involves multiple mechanisms independent of cyclooxygenase-2 inhibition.环氧化酶-2抑制剂及其类似物对人乳腺细胞中芳香化酶的抑制涉及多种独立于环氧化酶-2抑制作用的机制。
Steroids. 2008 Jan;73(1):104-11. doi: 10.1016/j.steroids.2007.09.011. Epub 2007 Oct 18.
5
Targeted chiral lipidomics analysis by liquid chromatography electron capture atmospheric pressure chemical ionization mass spectrometry (LC-ECAPCI/MS).通过液相色谱-电子捕获大气压化学电离质谱法（LC-ECAPCI/MS）进行靶向手性脂质组学分析。
Methods Enzymol. 2007;433:159-74. doi: 10.1016/S0076-6879(07)33009-7.
6
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.
7
Intracrinology of estrogens and androgens in breast carcinoma.乳腺癌中雌激素和雄激素的内分泌学
J Steroid Biochem Mol Biol. 2008 Feb;108(3-5):181-5. doi: 10.1016/j.jsbmb.2007.09.012. Epub 2007 Sep 6.
8
Elucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: the example of rat liver 3alpha-HSD (AKR1C9).阐明哺乳动物羟基类固醇脱氢酶（HSD）的完整动力学机制并确定反应坐标上的所有酶形式：以大鼠肝脏3α-HSD（AKR1C9）为例。
J Biol Chem. 2007 Nov 16;282(46):33484-33493. doi: 10.1074/jbc.M703414200. Epub 2007 Sep 11.
9
Exploiting the apoptotic actions of oestrogen to reverse antihormonal drug resistance in oestrogen receptor positive breast cancer patients.利用雌激素的凋亡作用来逆转雌激素受体阳性乳腺癌患者的抗激素耐药性。
Breast. 2007 Dec;16 Suppl 2(Suppl 2):S105-13. doi: 10.1016/j.breast.2007.07.020. Epub 2007 Aug 24.
10
Aromatase and COX in breast cancer: enzyme inhibitors and beyond.乳腺癌中的芳香化酶与环氧化酶：酶抑制剂及其他
J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):16-23. doi: 10.1016/j.jsbmb.2007.05.021. Epub 2007 May 25.
Zotero 插件