Pharmacological inhibition of 17β-hydroxysteroid dehydrogenase inhibits endometrial cancer growth in an orthotopic xenograft mouse model
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PROVIDER: PRJEB44184 | ENA |
REPOSITORIES: ENA
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Project description:Experimental design: Endometrial tumours were induced orthotopically (in one uterine horn) in 8-week-old female athymic nude mice (Crl:NU(NCr)-Foxn1nu), using an Ishikawa-derived cell line (clones Ishi-M3-HSDA, described in Konings et al 2018). This cell line maintains the characteristics of the parental line (i.e., gives rise to well differentiated-estrogen sensitive adenocarcinomas) and further bears the luciferase gene for in vivo measurement of tumour growth by bioluminescence and expresses the enzyme 17β-hydroxysteroid dehydrogenase (HSD17B1). After tumour engraftment (approximately two weeks), baseline was defined, mice were ovariectomised (to remove the natural source of estrogens) and estrone was supplemented via subcutaneous pellets at a dose of 0.02 g/day. Mice were further assigned to one arm, receiving only estrone, and a second arm, receiving estrone plus the HSD17B1 inhibitor FP4643 at a dose of 25mg/Kg. At humane endpoint (approximately 10 weeks), mice were sacrificed, primary tumours were excised and snap-frozen. Tumours were divided on their largest diameter plane and slices for RNA isolation were prepared from such largest surface area of the primary tumours. Histology on mirror slices confirmed the present of tumour tissue and the absence of necrosis, inflammation and mouse endometrium.
2021-04-09 | E-MTAB-10338 | biostudies-arrayexpress
Project description:17β-hydroxysteroid dehydrogenase-13 (17β-HSD13) is a liver-rich lipid droplet associated protein, encoding by gene HSD17B13, that acted as an important regulator of hepatic lipid metabolism. Increased expression of 17β-HSD13 promotes hepatic lipid accumulation in rodents, and a common loss-of-function variant of HSD17B13 (rs72613567: TA) is related to better outcome in patients with various chronic liver diseases. To understand the role of 17β-HSD13 in liver lipid metabolism under normal and high-fat feeding conditions, we characterized the effect of protein phosphorylation of 17β-HSD13 on hepatic lipid homeostasis. We identify Ser33 as an important protein kinase A (PKA)-mediated phosphorylation site of 17β-HSD13 that physically interact with ATGL and facilitates its translocation to lipid droplets to enhance lipolysis. Mutation of Ser33 to Ala (S33A) in 17β-HSD13 reduces ATGL-dependent lipolysis and increases lipid droplet size in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Consistently, a transgenic knock-in mouse strain carrying HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops liver steatosis with reduced lipolysis. Moreover, HSD17B1333A/A mice are more prone to high fat-induced hepatic steatosis and inflammation. Finally, we found Reproterol, a potential HSD17B13 modulator and FDA-approved drug, confers a protection against liver steatosis possibly through phosphorylation of 17β-HSD13 at Ser33 in a PKA-dependent manner. In summary, we demonstrate a critical role and the underlying mechanism of hepatic 17β-HSD13 phosphorylation in the pathogenesis of NAFLD. Our findings highlight the potential of targeting 17β-HSD13 phosphorylation as a novel therapeutic approach for NAFLD.
2023-03-11 | PXD037262 | Pride
Project description:17β-HSD1 expression modulates T47D transcript profile in in steroid-deprived medium. The enzyme specifically regulates apoptosis and cancer-related genes in T47D cells cultured in steroid-deprived medium. Genes that primarily involved in Cell cycle progression, such as the Cyclin A2 gene, CCNA2, are generally down-regulated whereas most genes involved in apoptosis and cell death, such as the proapoptotic gene XAF1 and FGF12, are on the contrary up-regulated by 17β-HSD1 knockdown, and 21% of the modulated genes belong to this latter functional category. This correborates with its role previously shown in increasing breast cancer cell proliferation (Aka et al, 2010) and indicates that in addition to its direct role as cell proliferation via incresing E2 and decreasing DHT, 17β-HSD1 may also be involved in oncogenesis by favoring its anti-apoptosis pathway in breast cancer cells 17β-HSD1 may also be involved in oncogenesis by favoring anti-apoptosis pathway and/or inhibiting cell survival pathway. We tested the ability of estrogen to induce or repress endogenous genes of T47D by microarray analysis. A total of 131 genes were found to increase or decrease 1.5-fold or higher in response to 17 beta-estradiol (1 nM for 48 h). Besides, the gene regulation occuring in steroid-deprived conditions showed that 17β-HSD1 modulates gene expression in steroid-independent manners. Our study thus demonstrates that 17β-HSD1 modulates the E2-independent transcription of endogenous genes in T47D cells. The E2-dependent transcription as well as the E2-independent transcription are significantly modulated by 17β-HSD1 in breast cancer cells We first report here that breast cancer cell transcript profile is independtly modulated by both 17β-HSD1 and its principale product estradiol.
2016-09-01 | GSE77345 | GEO
Project description:The maturation-inducing hormone 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) was first identified in the amago salmon. However, although carbonyl reductase-like 20beta-hydroxysteroid dehydrogenase (CR/20beta-HSD) was reported to convert 17alpha-hydroxyprogesterone (17alpha-P) to DHP in rainbow trout, we previously found that CR/20beta-HSD mRNA was not up-regulated in stimulated granulosa cells from masu salmon, which suggests that DHP is synthesized by a different enzyme. Accordingly, the present study aimed to identify the specific 20beta-hydroxysteroid dehydrogenase (20beta-HSD) responsible for DHP production by granulosa cells during final oocyte maturation in masu salmon. Granulosa layers were isolated from ovarian follicles at one month before ovulation and incubated with or without forskolin, which was used to mimic luteinizing hormone. Subsequent RNA-sequencing yielded ~12 million reads, with an average length of 51 bp, and 71,062 contigs of >100 bp were constructed. Of the 953 contigs that were exclusively constructed from the reads of forskolin-induced granulosa layers, tBlastx analysis identified one contig (#f103496) that matched 17beta-hydroxysteroid dehydrogenase type 12. We found that mammalian cells transfected with full-length omhsd17beta12l exhibited considerable 20beta-HSD activity, as indicated by efficient conversion of exogenous 17alpha-P to DHP. In addition, we found that omhsd17beta12l mRNA levels were consistently low in follicles during vitellogenic growth; however, the levels increased significantly during final oocyte maturation. The levels of omhsd17beta12l mRNA were also considerably increased in granulosa layers in which 20beta-HSD activity was induced by salmon pituitary extract. Therefore, we suggest that omhsd17beta12l, not CR/20beta-HSD, is the 20beta-HSD responsible for DHP production by granulosa cells in masu salmon during final oocyte maturation. Comparison of mRNA levels between control and forskolin-incubated sample.
2016-08-04 | E-GEOD-85134 | biostudies-arrayexpress
Project description:We used a functional small interfering RNA (siRNA) screen in ovarian cancer cells to identify 17β-hydroxysteroid dehydrogenase type 14 (HSD17B14) as a novel regulator of small EV secretion. We showed that the knockdown of HSD17B14 altered multiple gene expression in OVCAR8 cells.
2024-04-23 | GSE173253 | GEO
Project description:At the late 1940s, 17β-HSD1 was discovered as the first member of the 17β-HSD family with its gene cloned. The three-dimensional structure of human 17β-HSD1 is the first example of any human steroid converting enzyme. The human enzyme's structure and biological function have thus been studied extensively in the last two decades. In humans, the enzyme is expressed in placenta, ovary, endometrium and breast. The high activity of estrogen activation provides the basis of 17β-HSD1's implication in estrogen-dependent diseases, such as breast cancer, endometriosis and non-small cell lung carcinomas. Its dual function in estrogen activation and androgen inactivation has been revealed in molecular and breast cancer cell levels, significantly stimulating the proliferation of such cells. The enzyme's overexpression in breast cancer was demonstrated by clinical samples. Inhibition of human 17β-HSD1 led to xenograft tumor shrinkage. Unfortunately, through decades of studies, there is still no drug using the enzyme's inhibitors available. This is due to the difficulty to get rid of the estrogenic activity of its inhibitors, which are mostly estrogen analogues. New non-steroid inhibitors for the enzyme provide new hope for non-estrogenic inhibitors of the enzyme.
| S-EPMC6649686 | biostudies-literature
Project description:Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been observed to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compound for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 versus AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compounds were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was observed when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
| S-EPMC4414711 | biostudies-literature
Project description:Our previous studies have proved that 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) is a novel proliferation-promoting protein. The overexpression of HSD17B4 promotes hepatocellular carcinoma (HCC) cell proliferation. Vitamin K2 (VK2), a fat-soluble vitamin, has the function of promoting coagulation and can inhibit the progression of liver cancer. A previous study demonstrated that VK2 could bind to HSD17B4 in HepG2 cells. However, the mechanism of VK2 in inhibiting HCC cell proliferation is not clear. In this study, we investigate whether VK2 can inhibit the proliferation of HCC cell induced by HSD17B4 and the possible mechanism. We detected the effect of VK2 on HSD17B4-induced HCC cell proliferation, and the activation of STAT3, AKT, and MEK/ERK signaling pathways. We measured the effect of HSD17B4 on the growth of transplanted tumor and the inhibitory effect of VK2. Our results indicated that VK2 directly binds to HSD17B4, but does not affect the expression of HSD17B4, to inhibit the proliferation of HCC cells by inhibiting the activation of Akt and MEK/ERK signaling pathways, leading to decreased STAT3 activation. VK2 also inhibited the growth of HSD17B4-induced transplanted tumors. These findings provide a theoretical and experimental basis for possible future prevention and treatment of HCC using VK2.
| S-EPMC8630649 | biostudies-literature
Project description:17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in testes and seminal vesicles; it is also present in prostate tissue and involved in gonadal and non-gonadal testosterone biosynthesis. The enzyme is membrane-bound, and a crystal structure is not yet available. Selective aryl benzylamine-based inhibitors were designed and synthesised as potential agents for prostate cancer therapeutics through structure-based design, using a previously built homology model with docking studies. Potent, selective, low nanomolar IC50 17β-HSD3 inhibitors were discovered using N-(2-([2-(4-chlorophenoxy)phenylamino]methyl)phenyl)acetamide (1). The most potent compounds have IC50 values of approximately 75 nM. Compound 29, N-[2-(1-Acetylpiperidin-4-ylamino)benzyl]-N-[2-(4-chlorophenoxy)phenyl]acetamide, has an IC50 of 76 nM, while compound 30, N-(2-(1-[2-(4-chlorophenoxy)-phenylamino]ethyl)phenyl)acetamide, has an IC50 of 74 nM. Racemic C-allyl derivative 26 (IC50 of 520 nM) was easily formed from 1 in good yield and, to determine binding directionality, its enantiomers were separated by chiral chromatography. Absolute configuration was determined using single crystal X-ray crystallography. Only the S-(+)-enantiomer (32) was active with an IC50 of 370 nM. Binding directionality was predictable through our in silico docking studies, giving confidence to our model. Importantly, all novel inhibitors are selective over the type 2 isozyme of 17β-HSD2 and show <20% inhibition when tested at 10 µM. Lead compounds from this series are worthy of further optimisation and development as inhibitors of testosterone production by 17β-HSD3 and as inhibitors of prostate cancer cell growth.
| S-EPMC8659031 | biostudies-literature
Project description:Aldo-Keto-Reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase (HSD)/prostaglandin (PG) F2α 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-PGF2α to activate the FP receptor and deprives peroxisome proliferator activator receptorγ of its putative PGJ2 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.
| S-EPMC6422768 | biostudies-literature