Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Rižner, Tea Lanišnik; Penning, T.M.

doi:10.1016/j.steroids.2013.10.012

Cited by 177 publications

(147 citation statements)

References 108 publications

(211 reference statements)

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“…Key members of this family, AKR1C2 and AKR1D1, are known to bind and metabolize bile acids (43). AKR1D1 in particular catalyzes a key step in bile acid synthesis; deficiency can lead to cholestasis in humans (44).…”

Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedmentioning

confidence: 99%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Colorectal cancers (CRCs) account for nearly 10% of all cancer deaths in industrialized countries. Recent evidence points to a central role for the nuclear receptor liver receptor homolog-1 (LRH-1) in intestinal tumorigenesis. Interaction of LRH-1 with the Wnt/β-catenin pathway, highly active in a critical subpopulation of CRC cells, underscores the importance of elucidating LRH-1's role in this disease. Reduction of LRH-1 diminishes tumor burden in murine models of CRC; however, it is not known whether LRH-1 is required for tumorigenesis, for proliferation, or for both. In this work, we address this question through shRNA-mediated silencing of LRH-1 in established CRC cell lines. LRH-1 mRNA knockdown results in significantly impaired proliferation in a cell line highly expressing the receptor and more modest impairment in a cell line with moderate LRH-1 expression. Cell-cycle analysis shows prolongation of G0/G1 with LRH-1 silencing, consistent with LRH-1 cellcycle influences in other tissues. Cluster analysis of microarray gene expression demonstrates significant genome wide alterations with major effects in cell-cycle regulation, signal transduction, bile acid and cholesterol metabolism, and control of apoptosis. This study demonstrates a critical proproliferative role for LRH-1 in established colon cancer cell lines. LRH-1 exerts its effects via multiple signaling networks. Our results suggest that selected CRC patients could benefit from LRH-1 inhibitors.C olorectal cancer (CRC) accounts for nearly 10% of all cancer deaths in the United States. Much is understood about maintenance, but little is known about molecules driving initiation or metastasis of CRCs. Recent discoveries in animal and cellular models of CRC suggest a role for the nuclear receptor liver receptor homolog-1 (LRH-1, also known as NR5A2) (1).LRH-1, previously thought to be constitutively active, has a functional hormone-binding pocket that binds phosphatidylcholines (2, 3). The structure of the hormone-binding domain of LRH-1 has been determined with four different phospholipids in the binding pocket (4-6).LRH-1 is vital; knockout mouse embryos fail to undergo gastrulation (7). LRH-1 is expressed in the adult in the gastrointestinal tract, including liver and pancreas, and is also present in ovaries, where it regulates steroidogenesis (8). It is highly expressed in intestinal crypts where it is believed to play a role in intestinal epithelial cell renewal (9). LRH-1 has prominent roles in development, metabolism, stem-cell pluripotency, and tumorigenesis (10-14).LRH-1 figures prominently in WNT signaling in the intestine (9, 13). The WNT gene family is a large, conserved signaling pathway with roles in development, cellular homeostasis, and tumorigenesis (15). WNT signaling activates β-catenin, an important transcriptional coactivator that is active in over 80% of CRCs (16). LRH-1 physically binds to β-catenin and functions synergistically in the regulation of certain target genes, including cyclin E1 (9).LRH-1 and β-catenin contribute to ...

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Section: Antiproliferative Mechanism Of Lrh-1 Inhibition Is Conservedmentioning

confidence: 99%

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Bayrer

Mukkamala

Sablin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The enzyme of AKR1C2 has the predominant catalytic efficiency. Rižner & Penning (2014) reviewed the possible roles of AKR1 enzymes in human steroid metabolism and alluded on the possibility of AKR1C gene expression in endometrial carcinoma. However, AKR1C1 and AKR1C2 mRNA expression in cancerous endometrium did not differ significantly to that in adjacent control normal tissue (Smuc & Rizner 2009, Sinreih et al 2013.…”

Section: :7mentioning

confidence: 99%

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Itō¹,

Miki²,

Suzuki³

et al. 2016

Endocrine-Related Cancer

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In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

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“…Both human AKR1C isoforms, AKR1C1 and AKR1C2 can metabolize dydrogesterone with high efficacy, whereas AKR1C3 is less active (Beranič et al 2011(Beranič et al , 2012. Interestingly, although dydrogesterone is close in structure to progesterone, it is metabolized by AKR enzymes only to 20α-DHD, whereas progesterone is transformed to several products including 5α-pregnane, 5β-pregnane and 4-pregnene metabolites (Rižner & Penning 2014). Recently, Olbrich et al (2016) showed an involvement of cytochrome P450 isozymes in the metabolism of dydrogesterone.…”

Section: Metabolism Of Progestinsmentioning

confidence: 99%

“…In peripheral tissues, AKR1C1 and AKR1C2 form 3β-hydroxytibolone which exhibits estrogenic activity, whereas in liver, TIB is reduced to 3α-hydroxytibolone by AKR1C4 which functions predominantly as 3α-hydroxysteroid dehydrogenase (Steckelbroeck et al 2004). This explains why 3α-hydroxytibolone is the major circulating metabolite, whereas 3β-hydroxytibolone is the major metabolite in target tissues (Penning et al 2014). Interestingly, AKR1C2 exhibits different stereochemical preference depending on the ketosteroid substrate.…”

Section: Metabolism Of Progestinsmentioning

confidence: 99%

“…Interestingly, AKR1C2 exhibits different stereochemical preference depending on the ketosteroid substrate. Indeed, it produces 3α-products with the potent androgen 5α-dihydrotestosterone (5α-DHT) behaving as an efficient 3α-hydroxysteroid dehydrogenase, whereas it inverts its stereospecificity with TIB acting as a 3β-hydroxysteroid dehydrogenase (Steckelbroeck et al 2004, Rižner & Penning 2014. Finally, TIB can also be metabolized, in less amount, to the potent estrogen 7α-methylethinylestradiol (Wiegratz et al 2002).…”

Section: Metabolism Of Progestinsmentioning

confidence: 99%

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The other side of progestins: effects in the brain

Giatti

Melcangi

Pesaresi

2016

Journal of Molecular Endocrinology

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Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.

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Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Cited by 177 publications

References 108 publications

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

The other side of progestins: effects in the brain

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