Aldo-keto reductase family member C3(AKR1C3)promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α

Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.

Study of Aldo-keto Reductase 1C3 Inhibitor with Novel Framework for Treating Leukaemia Based on Virtual Screening and In vitro Biological Activity Testing

Aldo-keto reductase 1C3(AKR1C3)is a potential target for the treatment of acute myeloid leukaemia and T-cell acute lymphoblastic leukaemia.In this study,pharmacophore models,molecular docking and virtual screening of target prediction were used to find a potential AKR1C3 inhibitor.Firstly,eight bacteriocin derivatives(Z1-Z8)were selected as training sets to construct 20 pharmacophore models.The best pharmacophore model MODEL_016 was obtained by Decoy test(the enrichment degree was 21.5117,and the fitting optimisation degree was 0.9668).Secondly,MODEL_016 was used for the virtual screening of ZINC database.Thirdly,the hit 83256 molecules were docked into the AKR1C3 protein.Compared to the total scores and interactions between compounds and protein,16532 candidate compounds with higher docking scores and interactions with important residues PHE306 and TRP227 were screened.Lastly,eight compounds(A1-A8)that had good absorption,distribution,metabolism,excretion and toxicity(ADMET)properties were obtained by target prediction.Compounds A3 and A7 with high total score and good target prediction results were selected for in vitro biological activity test,whose IC_(50) values were 268.3 and 88.94µmol/L,respectively.The results provide an important foundation for the discovery of novel AKR1C3 inhibitors.The research methods used in this study can also provide important references for the research and development of new drugs.

Berberine inhibits androgen synthesis by interaction with aldo-keto reductase 1C3 in 22Rv1 prostate cancer cells

AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aido-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rvl cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family I member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family I member C3 enzyme activity and the inhibition of 22Rvl prostate cancer cell growth by decreasing the intfacellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKRlC3 inhibitors using berberine as the lead compound.

Primary 4-3-oxosteroid 5β-reductase deficiency:Two cases in China

Aldo-keto reductase 1D1(AKR1D1) deficiency,a rare but life-threatening form of bile acid deficiency,has not been previously described in China.Here,we describe the first two primary 4-3-oxosteroid 5β-reductase deficiency patients in China's Mainland diagnosed by fast atom bombardment-mass spectroscopy of urinary bile acids and confirmed by genetic analysis.A high proportion of atypical 3-oxo-4-bile acids in the urine indicated a deficiency in 4-3-oxosteroid 5β-reductase.All of the coding exons and adjacent intronic sequence of the AKR1D1 gene were sequenced using peripheral lymphocyte genomic DNA of two patients and one of the patient's parents.One patient exhibited compound heterozygous mutations:c.396C>A and c.722A>T,while the other was heterozygous for the mutation c.797G>A.Based on these mutations,a diagnosis of primary 4-3-oxosteroid 5β-reductase deficiency could be confirmed.With ursodeoxycholic acid treatment and fat-soluble vitamin supplements,liver function tests normalized rapidly,and the degree of hepatomegaly was markedly reduced in both patients.

Intracrine androgen biosynthesis and drug resistance

Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor(AR)signaling.Current therapies use AR signaling inhibitors(ARSI)exemplified by abiraterone acetate,a P450c17 inhibitor,and enzalutamide,a potent AR antagonist.However,drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months.Multiple mechanisms can contribute to ARSI drug resistance.These mechanisms can include but are not limited to germline mutations in the AR,post-transcriptional alterations in AR structure,and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor.This review focuses on intracrine androgen biosynthesis,how this can contribute to ARSI drug resistance,and therapeutic strategies that can be used to surmount these resistance mechanisms.