Important roles of the AKR1C2 and SRD5A1 enzymes in progesterone metabolism in endometrial cancer model cell lines

Sinreih, Maša; Anko, Maja; Zukunft, Sven; Adamski, Jerzy; Rižner, Tea Lanišnik

doi:10.1016/j.cbi.2014.11.012

Cited by 33 publications

(20 citation statements)

References 28 publications

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“…AKR1C1 played crucial roles in progesterone metabolism, and contributed to the treatment of pregnancy maintenance (Sinreih et al, 2015). We designed the study of finding AKR1C1 inhibitor based on purification of AKR1C1 enzymes from E. coli followed by conducting enzymatic assay, which is a classic method in screening inhibitors of AKR1C1 (El-Kabbani et al, 2010; Zheng et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Liquiritin, as a Natural Inhibitor of AKR1C1, Could Interfere With the Progesterone Metabolism

Zeng

Zhu²,

You³

et al. 2019

Front. Physiol.

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Low progesterone level is always linked with pre-term birth. Therefore, maintaining of progesterone level is vital during pregnancy. Aldo-keto reductase family one member C1 (AKR1C1) catalyzes the reduction of progesterone to its inactive form of 20-alpha-hydroxy-progesterone and thus limits the biological effect of progesterone. In our effort to identify the natural compound that would specifically inhibit AKR1C1, liquiritin was found to be a selective and potent inhibitor of AKR1C1. Kinetic analyses in the S-(+)-1,2,3,4-tetrahydro-1-naphthol (s-tetralol) catalyzed by AKR1C1 in the presence of the inhibitors suggest that liquiritin is a competitive inhibitor by targeting the residues Ala-27, Val-29, Ala-25, and Asn-56 of AKR1C1. In HEC-1-B cells, treatment with liquiritin results in 85.00% of reduction in progesterone metabolism, which is mediated by AKR1C1 enzymatic activity. Overall, our study not only identify liquiritin as an inhibitor against AKR1C1, but also reveal that liquiritin may be served as a potential intervention strategy for preventing pre-term birth caused by low progesterone level.

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Section: Resultsmentioning

confidence: 99%

Liquiritin, as a Natural Inhibitor of AKR1C1, Could Interfere With the Progesterone Metabolism

Zeng

Zhu²,

You³

et al. 2019

Front. Physiol.

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“…Cytoplasmic AKRs (AKR1C1, 1C2, 1C3/17βHSD5 and 1C4) have broad substrate specificity with non-stereo-selective 3α/3βHSD, 17- and 20-ketosteroid reductase activities (Table 2 ; Penning et al, 2004 ; Steckelbroeck et al, 2010 ). Together with the fact that they have wide tissue distribution (only AKR1C4 is restricted), AKR1Cs contribute to make intracrine networks flexible and intricate (Rižner and Penning, 2014 ; Sinreih et al, 2014 ).…”

Section: From Ovarian Estrogen Synthesis To Intracrinologymentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

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Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

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“…While AKR1C4 and AKR1C3 are almost exclusively in the liver and prostate respectively, AKR1C1 and AKR1C2 are most prominent in the mammary glands includes breast cancer, endometrial cancer, colorectal cancer (Hanada et al, 2012; Hofman et al, 2015; Sinreih et al, 2015b; Wang et al, 2016; Wenners et al, 2016). AKR1C2, is also known as bile-acid binding protein and DD2, has lower catalytic efficiencies but preferentially reduces 3-ketosteroids.…”

Section: Akr1c1–c4-hydroxysteroid Dehydrogenasementioning

confidence: 99%

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

et al. 2017

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Aldo–keto reductases comprise of AKR1C1–AKR1C4, four enzymes that catalyze NADPH dependent reductions and have been implicated in biosynthesis, intermediary metabolism, and detoxification. Recent studies have provided evidences of strong correlation between the expression levels of these family members and the malignant transformation as well as the resistance to cancer therapy. Mechanistically, most studies focus on the catalytic-dependent function of AKR1C isoforms, like their impeccable roles in prostate cancer, breast cancer, and drug resistance due to the broad substrates specificity. However, accumulating clues showed that catalytic-independent functions also played critical roles in regulating biological events. This review summarizes the catalytic-dependent and -independent roles of AKR1Cs, as well as the small molecule inhibitors targeting these family members.

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Important roles of the AKR1C2 and SRD5A1 enzymes in progesterone metabolism in endometrial cancer model cell lines

Cited by 33 publications

References 28 publications

Liquiritin, as a Natural Inhibitor of AKR1C1, Could Interfere With the Progesterone Metabolism

Liquiritin, as a Natural Inhibitor of AKR1C1, Could Interfere With the Progesterone Metabolism

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

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