Affinage

AKR1C3

Aldo-keto reductase family 1 member C3 · UniProt P42330

Length
323 aa
Mass
36.9 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKR1C3 is a multifunctional, NADPH-dependent aldo-keto reductase that shapes intracellular hormone and prostaglandin milieus and, through both catalytic and non-enzymatic activities, drives proliferative and drug-resistant programs in hormone-dependent cancers (PMID:11165022, PMID:23995860). Enzymatically it operates as a 3-, 17-, and 20-ketosteroid reductase, converting androstenedione and 5α-androstanedione to testosterone and DHT (with kinetic preference for 5α-reduced substrates) and additionally reducing 11-oxygenated androgens with even greater efficiency, while inactivating progesterone (PMID:11165022, PMID:35560164). It also functions as a prostaglandin F synthase, converting PGD2 to 9α,11β-PGF2α and PGH2 to PGF2α by direct hydride transfer from bound NADPH to the endoperoxide without catalytic residue participation, generating products that signal through the FP receptor and PI3K/Akt or ERK/CREB pathways (PMID:16475787, PMID:18508192, PMID:26170067). Beyond catalysis, AKR1C3 acts as a non-enzymatic, AR-selective coactivator: it physically binds full-length AR and the AR-V7 splice variant, co-occupies androgen-responsive promoters, and stabilizes these receptors against ubiquitin-mediated degradation; catalytically inactive AKR1C3 retains this function and likewise stabilizes the ubiquitin ligase Siah2 and PARP1 (PMID:23995860, PMID:26160177, PMID:31308078, PMID:35773412, PMID:36799021). In prostate cancer it sustains intratumoral androgen synthesis and AR/AR-V7 activity, conferring resistance to enzalutamide, abiraterone, apalutamide, and darolutamide (PMID:25649766, PMID:27794047, PMID:32430485). AKR1C3 expression is transcriptionally activated by ERG (TMPRSS2-ERG fusions), AR itself, the NRF2/MAFG heterodimer, and the AHR, and is induced by insulin via a PI3K/AKT/mTOR/NRF2 axis in adipocytes (PMID:25754347, PMID:31253396, PMID:35773412, PMID:36596844, PMID:36799021). In hepatocellular carcinoma it drives proliferation and metastasis through an NF-κB/STAT3 positive feedback loop, suppresses ferroptosis via YAP/SLC7A11 signaling, and sustains lipid-droplet accumulation that protects from sorafenib-induced mitochondrial lipotoxicity (PMID:33361392, PMID:36920042, PMID:36451864). AKR1C3 also activates the nitrogen-mustard prodrug PR-104A, making its expression a determinant of prodrug sensitivity (PMID:26116659).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Establishing AKR1C3's intrinsic catalytic repertoire was the foundational question; reconstitution defined it as a broad-specificity hydroxysteroid oxidoreductase capable of generating active androgens.

    Evidence In vitro assays with homogeneous recombinant enzyme and kinetic analysis across multiple steroid substrates

    PMID:11165022

    Open questions at the time
    • Did not address physiological tissue context or in-cell flux
    • Did not distinguish dominant in vivo reaction direction
  2. 2006 High

    How AKR1C3 catalyzes prostaglandin reduction was resolved structurally, showing direct NADPH hydride transfer to PGH2 without catalytic residues and mapping the PGD2/inhibitor binding site.

    Evidence X-ray crystallography at 2.0 Å with NADPH and bimatoprost plus inhibition assays

    PMID:16475787

    Open questions at the time
    • Did not connect PGF synthase activity to a cellular phenotype
  3. 2008 Medium

    The functional consequence of PGD2 reduction was defined: AKR1C3-generated 9α,11β-PGF2α drives proliferation through FP receptor and PI3K/Akt signaling.

    Evidence Stable AKR1C3 overexpression in PC-3 cells with FP antagonist and PI3K inhibitor dissection

    PMID:18508192

    Open questions at the time
    • Single overexpression model
    • Did not establish endogenous requirement
  4. 2009 High

    Whether AKR1C3 contributes to physiological androgen output was tested, establishing it as a mediator of adrenal testosterone production.

    Evidence siRNA knockdown in H295R adrenal cells plus in vivo adrenal vein sampling with ACTH

    PMID:19336506

    Open questions at the time
    • Did not quantify AKR1C3's relative contribution versus other steroidogenic enzymes
  5. 2012 High

    Structural definition of the androstenedione-binding site and selectivity subpocket enabled rational design of AKR1C3-selective inhibitors over AKR1C1/AKR1C2.

    Evidence Crystallography of AKR1C3·NADP+·inhibitor complexes with enzymatic and AR reporter assays

    PMID:22507964 PMID:23432095

    Open questions at the time
    • Inhibitor in vivo efficacy not established at this stage
  6. 2012 Medium

    Upstream regulation by growth/differentiation signaling was probed, identifying an activin A–AKR1C3–androgen feedback loop in prostate cancer.

    Evidence Activin A treatment and antagonism in prostate cancer cell lines and xenografts with testosterone measurement

    PMID:23024260

    Open questions at the time
    • Direct transcriptional mechanism not defined
    • Single-lab finding
  7. 2013 High

    The pivotal discovery that AKR1C3 functions beyond catalysis: it physically interacts with AR and acts as an AR-selective coactivator promoting growth independently of steroidogenesis.

    Evidence Co-IP, ChIP, confocal co-localization, xenograft growth, and selective inhibitor treatment

    PMID:23995860

    Open questions at the time
    • Structural basis of AR binding unresolved
    • Coactivator domain not mapped
  8. 2015 High

    The non-enzymatic role was mechanistically extended: AKR1C3 stabilizes the ubiquitin ligase Siah2 to enhance AR activity, with catalytically dead enzyme retaining function.

    Evidence Co-IP, Siah2 knockdown/re-expression of WT and catalytic-dead AKR1C3, ubiquitination and tumor assays

    PMID:26160177

    Open questions at the time
    • Did not define the AKR1C3 surface mediating Siah2 binding
  9. 2015 High

    AKR1C3 was established as a clinically relevant driver of antiandrogen resistance via intracrine androgen synthesis and as a transcriptional target of TMPRSS2-ERG fusions.

    Evidence shRNA/overexpression, LC/MS androgen quantitation, ERG ChIP-seq, and in vivo drug sensitivity assays

    PMID:25649766 PMID:25754347

    Open questions at the time
    • Relative weight of catalytic versus coactivator contribution to resistance not partitioned
  10. 2015 High

    AKR1C3's role beyond prostate was broadened: it activates the prodrug PR-104A, determining chemotherapeutic sensitivity, and its PGD2-derived metabolite drives breast cancer signaling and chemoresistance.

    Evidence AKR1C3 overexpression-driven PR-104 sensitization in leukemia PDX; 11β-PGF2α/FP/ERK-CREB-Slug pathway in FP-expressing MCF-7

    PMID:26116659 PMID:26170067

    Open questions at the time
    • PR-104A activation chemistry not structurally detailed here
  11. 2015 High

    Endocrine regulation in adipose tissue was defined: insulin upregulates AKR1C3 to increase testosterone generation, linking hyperinsulinemia to hyperandrogenism.

    Evidence Insulin treatment of adipocytes with LC-MS/MS androgen measurement and in vivo DHEA challenge in insulin-receptor-mutation subjects

    PMID:26312838

    Open questions at the time
    • Transcription factor mediating insulin induction not yet identified at this step
  12. 2016 High

    AKR1C3 was shown to mediate abiraterone resistance, generalizing its role across AR-pathway inhibitors and validating indomethacin as a resensitizing agent.

    Evidence Bidirectional overexpression/knockdown, androgen and AR activity measurement, in vivo indomethacin treatment

    PMID:27794047

    Open questions at the time
    • Did not address AR-V7 contribution at this stage
  13. 2019 High

    The resistance mechanism was extended to AR-V7: AKR1C3 stabilizes the AR-V7 splice variant via the ubiquitin-proteasome pathway, with inhibition lowering AR/AR-V7 protein.

    Evidence Co-IP of AKR1C3-AR-V7, proteasome pathway analysis, indomethacin treatment, in vivo xenografts

    PMID:31308078

    Open questions at the time
    • Mechanism of stabilization (E3 ligase competition or chaperoning) not resolved
  14. 2020 Medium

    The AKR1C3/AR-V7 axis was shown to drive cross-resistance to multiple antiandrogens and to repress the tumor suppressor B4GALT1 via reciprocal protein stabilization.

    Evidence shRNA epistasis across enzalutamide/apalutamide/darolutamide; Co-IP and B4GALT1 analysis in CRPC models

    PMID:32430485 PMID:32902124

    Open questions at the time
    • Single-lab findings
    • Reciprocal stabilization mechanism not biochemically dissected
  15. 2020 High

    AKR1C3 was implicated in hepatocellular carcinoma through a self-reinforcing inflammatory circuit: it activates NF-κB via TRAF6, and STAT3 transcriptionally feeds back onto the AKR1C3 promoter.

    Evidence Gain/loss-of-function, NF-κB reporters, TRAF6 ubiquitination, STAT3 ChIP, in vivo assays

    PMID:33361392

    Open questions at the time
    • Whether catalytic activity is required for TRAF6 modulation not isolated
  16. 2021 Medium

    Additional upstream activators were identified — AHR and PAH/EGFR signaling — linking environmental and xenobiotic exposure to AKR1C3 induction and doxorubicin resistance.

    Evidence AhR CRISPR knockout and promoter reporter in TNBC; EGFR inhibition, mutational and docking analysis with benzo[a]pyrene

    PMID:31253396 PMID:34991250

    Open questions at the time
    • Single-lab findings
    • Integration with other AKR1C3 promoter inputs not modeled
  17. 2022 High

    Transcriptional control by NRF2/MAFG was established alongside a new non-enzymatic effector role, AKR1C3-mediated PARP1 stabilization driving HCC growth.

    Evidence NRF2/MAFG ChIP on AKR1C3 promoter, WT vs catalytic-mutant overexpression, PARP1 ubiquitination, in vivo assays

    PMID:35773412

    Open questions at the time
    • Direct AKR1C3-PARP1 binding interface not defined
  18. 2022 High

    AKR1C3's metabolic role in HCC was defined: it sustains lipid-droplet formation that buffers cells against sorafenib-induced mitochondrial lipotoxicity.

    Evidence CRISPR knockout, isotopic tracing, multi-omics, Seahorse flux analysis, and inhibitor treatment

    PMID:36451864

    Open questions at the time
    • Enzymatic substrate driving lipid-droplet phenotype not pinpointed
  19. 2022 High

    The biochemical scope of AKR1C3 androgen synthesis was refined to include kinetically superior reduction of 11-oxygenated androgens, relevant to PCOS hyperandrogenism.

    Evidence HPLC kinetic assays with recombinant AKR1C3 and isotope-dilution LC-HRMS in insulin-treated adipocytes

    PMID:35560164

    Open questions at the time
    • In vivo dominance of 11-oxygenated versus classical pathway not quantified
  20. 2023 High

    Integration of the coactivator and metabolic roles was achieved: AKR1C3 non-enzymatically stabilizes AR to induce FASN and lipid droplets via PI3K/AKT/mTOR/NRF2, with bifunctional inhibitors required to block this output.

    Evidence Co-IP, proximity ligation, ChIP-qPCR co-occupancy at FASN, pathway inhibition, and monofunctional vs bifunctional inhibitor comparison

    PMID:36799021

    Open questions at the time
    • Coactivator-deficient separation-of-function mutants not used
  21. 2023 Medium

    AR was shown to reciprocally regulate AKR1C3 through a distal enhancer, closing a feed-forward loop, and dual inhibitors (PTUPB) synergized with enzalutamide to suppress CRPC.

    Evidence AR ChIP on AKR1C3 enhancer, enzymatic assays, and VCaP/PDX organoid combination drug studies

    PMID:36596844

    Open questions at the time
    • Single-lab finding
    • Enhancer interaction with NRF2/ERG inputs not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AKR1C3 mechanistically distinguishes and balances its enzymatic versus AR/Siah2/PARP1-stabilizing coactivator functions — and the structural basis of its protein-protein interactions — remains unresolved.
  • No structure of AKR1C3 bound to AR, Siah2, or PARP1
  • Separation-of-function mutants distinguishing coactivator from catalytic roles not defined
  • In vivo dominance of competing downstream programs unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 2 GO:0016209 antioxidant activity 1
Localization
GO:0005634 nucleus 2 GO:0005811 lipid droplet 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ARAR-V7PARP1SIAH2TRAF6

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Recombinant AKR1C3 expressed in E. coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3α-, 17β- and 20α-hydroxysteroid oxidase in vitro, reducing 5α-DHT, androstenedione, estrone and progesterone to produce 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxyprogesterone respectively; kinetic analysis (kcat/Km) showed preference for 5α-dihydrotestosterone and 5α-androstane-3,17-dione as substrates. In vitro enzymatic assay with homogeneous recombinant protein expressed in E. coli; kinetic analysis (kcat/Km); RT-PCR for tissue distribution Molecular and cellular endocrinology High 11165022
2006 Crystal structure of prostaglandin F synthase (AKR1C3/PGFS) containing NADPH and bimatoprost at 2.0 Å resolution revealed the PGD2 binding site and proposed catalytic mechanism: PGF2α formation from PGH2 involves direct hydride transfer from bound NADPH to the 9,11-endoperoxide of PGH2 without participation of specific amino acid residues; bimatoprost binds near the PGD2 site with reversed chain orientation. X-ray crystallography (2.0 Å resolution), inhibition assays, model building Biochemistry High 16475787
2008 AKR1C3 converts PGD2 to 9α,11β-PGF2α via 11-ketoprostaglandin reductase activity; overexpression of AKR1C3 in PC-3 prostate cancer cells elevated cell proliferation in response to PGD2 stimulation; this proliferative signaling was mediated through the FP (prostaglandin F) receptor and downstream PI3K/Akt pathway. Stable transfection of PC-3 cells with AKR1C3 cDNA; cell proliferation assays; FP receptor antagonist (AL8810); PI3K inhibitor (LY294002); Western blot for Akt phosphorylation Molecular and cellular endocrinology Medium 18508192
2009 AKR1C3 is expressed in human adrenal zona reticularis and mediates adrenal testosterone production: siRNA knockdown of AKR1C3 in H295R adrenal cells significantly inhibited testosterone production, and ACTH stimulation increased adrenal vein testosterone levels in vivo. siRNA knockdown in H295R cells; testosterone measurement; adrenal vein sampling with ACTH stimulation; microarray, RT-PCR, immunohistochemistry The Journal of clinical endocrinology and metabolism High 19336506
2012 Crystal structures of AKR1C3 in complex with NADP+ and two inhibitor compounds (an N-(aryl)amino-benzoate and a bifunctional inhibitor/AR antagonist) revealed that inhibitors bind in the androstenedione-binding site; one compound forms a unique 'double-decker' structure; a phenylamino ring projecting into a subpocket confers selectivity over AKR1C1/AKR1C2. X-ray crystallography of AKR1C3·NADP+·inhibitor complexes; enzymatic inhibition assays; AR reporter gene assays; Western blot Bioorganic & medicinal chemistry letters High 22507964
2013 AKR1C3 acts as a novel androgen receptor (AR)-selective enzymatic coactivator: it physically interacts with AR (demonstrated by co-immunoprecipitation), co-localizes with AR in prostate cancer cells and xenografts, is recruited to the promoter of an androgen-responsive gene (ChIP), and its coactivator function promotes prostate cancer cell and xenograft growth independently of its steroidogenic activity. Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); confocal microscopy; stable transfection; xenograft growth assays; AR transactivation reporter assays; selective AKR1C3 inhibitor treatment Clinical cancer research High 23995860
2013 Crystal structure of AKR1C3·NADP+·2'-des-methyl-indomethacin complex revealed a unique inhibitor binding mode, enabling rational design of indomethacin analogues with nanomolar potency, >100-fold selectivity over AKR1C1/AKR1C2, and blocking of testosterone formation in LNCaP-AKR1C3 cells. X-ray crystallography; enzymatic inhibition assays; cell-based testosterone formation assay Journal of medicinal chemistry High 23432095
2015 AKR1C3 mediates resistance to enzalutamide in prostate cancer through intracrine androgen synthesis: shRNA knockdown or indomethacin inhibition of AKR1C3 resensitized enzalutamide-resistant cells to enzalutamide both in vitro and in vivo; overexpression of AKR1C3 was sufficient to confer resistance; LC/MS analysis confirmed elevated androgen precursors and androgens in resistant cells. shRNA knockdown; AKR1C3 overexpression; global gene expression analysis; LC/MS metabolite analysis; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin inhibition Cancer research High 25649766
2015 ERG (from TMPRSS2-ERG fusion) directly binds the AKR1C3 gene and regulates its expression; ERG knockdown reduced AKR1C3 expression, decreased DHT synthesis from 5α-androstanedione, and reduced PSA expression in VCaP cells, establishing an ERG/AKR1C3/AR feed-forward loop in prostate cancer. Lentivirus-mediated ERG knockdown; ChIP-seq (ERG binding to AKR1C3 gene); LC-MS androgen quantitation; gene expression analysis; immunohistochemistry Clinical cancer research High 25754347
2015 AKR1C3 stabilizes the ubiquitin ligase Siah2 by physically binding to Siah2 and inhibiting its self-ubiquitination and degradation, thereby enhancing Siah2-dependent AR transcriptional activity in prostate cancer cells; both wild-type and catalytically inactive AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, indicating a non-enzymatic role. Co-immunoprecipitation (AKR1C3-Siah2 interaction); Siah2 knockdown with re-expression of WT and catalytically inactive AKR1C3; ubiquitination assays; in vitro and orthotopic tumor growth assays; androgen level measurement The Journal of biological chemistry High 26160177
2015 Insulin upregulates AKR1C3 expression and activity in subcutaneous adipocytes in vitro, driving increased testosterone generation from androstenedione; in vivo DHEA challenge in women with insulin receptor mutations showed elevated testosterone production correlating with AKR1C3 induction. In vitro insulin treatment of differentiated adipocytes; AKR1C3 expression by real-time PCR; androgen measurement by LC-MS/MS; in vivo DHEA challenge with serial blood androgen measurement Lancet High 26312838
2016 AKR1C3 activation is a critical mechanism of resistance to abiraterone: overexpression of AKR1C3 conferred abiraterone resistance while downregulation resensitized resistant cells; AKR1C3 increases intracrine androgen synthesis and enhances AR transcriptional activity in abiraterone-resistant cells; indomethacin treatment overcame resistance both in vitro and in vivo. AKR1C3 overexpression and shRNA knockdown; intracrine androgen measurement; AR transcriptional activity assays; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin treatment Molecular cancer therapeutics High 27794047
2019 AKR1C3 increases AR-V7 protein stability in enzalutamide-resistant prostate cancer cells through the ubiquitin-mediated proteasome pathway; the AKR1C3/AR-V7 complex collaboratively confers resistance to AR-targeted therapies; indomethacin targeting AKR1C3 decreases AR/AR-V7 protein expression both in vitro and in vivo. Co-immunoprecipitation (AKR1C3-AR-V7 interaction); proteasome pathway analysis; indomethacin treatment; Western blot; bioinformatic pathway analysis; in vivo xenograft studies Molecular cancer therapeutics High 31308078
2020 AKR1C3 promotes HCC cell proliferation and metastasis by activating NF-κB signaling through modulation of TRAF6 and inducing its autoubiquitination; activated NF-κB releases proinflammatory factors that phosphorylate STAT3; STAT3 directly binds the AKR1C3 promoter and increases AKR1C3 transcription, forming a positive feedback loop; AKR1C3/NF-κB/STAT3 axis was validated by gain- and loss-of-function experiments. Gain- and loss-of-function experiments (overexpression and knockdown); NF-κB reporter assays; TRAF6 ubiquitination assays; STAT3 ChIP on AKR1C3 promoter; in vitro and in vivo (xenograft) proliferation and invasion assays; AKR1C3 inhibitor treatment Cancer research High 33361392
2020 The AKR1C3/AR-V7 axis confers cross-resistance to enzalutamide, abiraterone, apalutamide, and darolutamide; knockdown of AR-V7 resensitized enzalutamide-resistant cells to apalutamide and darolutamide; targeting AKR1C3 resensitized resistant cells through AR-V7 inhibition. shRNA knockdown of AR-V7 and AKR1C3; drug sensitivity assays; gene expression analysis Molecular cancer therapeutics Medium 32430485
2020 AKR1C3/AR-V7 complex maintains CRPC tumor growth by repressing B4GALT1 (a tumor suppressor gene) expression; AKR1C3 interacts with AR-V7 protein in CRPC cells and reciprocally inhibits AR-V7 and AKR1C3 protein degradation. Co-immunoprecipitation; immunohistochemistry in clinical specimens; in vitro and in vivo (xenograft) tumor growth assays; B4GALT1 expression analysis Journal of cellular and molecular medicine Medium 32902124
2021 AHR (aryl hydrocarbon receptor) transcriptionally activates AKR1C3 expression in triple-negative breast cancer cells: AhR knockout decreased AKR1C3 expression; AhR enhanced AKR1C3 promoter reporter activity; reduced AKR1C3 enhanced doxorubicin sensitivity, linking AhR→AKR1C3→doxorubicin resistance. AhR CRISPR/Cas9 knockout; AKR1C3 promoter reporter assay; AKR1C3 siRNA knockdown; cell viability assays with doxorubicin; Western blot Biochemical and biophysical research communications Medium 31253396
2021 PAH exposure (benzo[a]pyrene) induces AKR1C3 expression and 11-ketoreduction of prostaglandin D2 through an EGFR-dependent pathway: B[a]P causes c-Src-mediated EGFR phosphorylation and auto/paracrine EGFR activation; EGFR inhibition blocks B[a]P-induced AKR1C3 upregulation; DLCs (PCB126) block EGFR activation by binding its extracellular domain, explaining differential AHR ligand responses. EGFR inhibition; receptor binding and internalization assays; mutational amino acid exchange; docking analyses; nanopore long-read RNA-seq; kinase inhibitor studies Environment international Medium 34991250
2022 AKR1C3-dependent lipid droplet (LD) formation is required for sorafenib resistance in HCC: CRISPR/Cas9 knockout of AKR1C3 fully depletes LD contents and redirects FA flux to phospholipids, sphingolipids, and mitochondria; AKR1C3-dependent LD accumulation protects cells from sorafenib-induced mitochondrial lipotoxicity; pharmacological inhibition of AKR1C3 induces autophagy-dependent LD catabolism, mitochondrial fission, and apoptosis. CRISPR/Cas9 gene editing; isotopic tracing with deuterium-labeled palmitate and 13C-labeled glucose; proteomics and metabolomics; Seahorse metabolic flux analysis; immunoblotting; immunofluorescence; AKR1C3 inhibitor treatment Theranostics High 36451864
2022 NRF2/MAFG transcription factor heterodimer directly binds the AKR1C3 promoter to activate its transcription; AKR1C3 in turn stabilizes PARP1 by decreasing its ubiquitination, promoting HCC cell proliferation; both catalytic and non-catalytic AKR1C3 functions drive tumor growth. ChIP (NRF2/MAFG binding to AKR1C3 promoter); AKR1C3 WT and catalytic mutant overexpression; PARP1 ubiquitination assay; in vitro and in vivo xenograft assays; AKR1C3 shRNA intratumoral injection Oncogene High 35773412
2022 Insulin-induced AKR1C3 in PCOS adipocytes converts both classical (androstenedione→testosterone) and 11-oxygenated androgens (11K-4AD→11K-T; 11K-5AD→11K-DHT) to potent androgens; conversion of 11-oxygenated androgens was kinetically superior to classical androgen formation by recombinant AKR1C3; 11K-T formed in adipocytes is subsequently inactivated by HSD11B1. HPLC discontinuous kinetic assays with recombinant AKR1C3; stable isotope dilution LC-HRMS quantitation of androgens in insulin-treated SGBS adipocytes; AKR1C3-deficient cell experiments Endocrinology High 35560164
2023 AKR1C3 suppresses ferroptosis in HCC through YAP/SLC7A11 signaling: AKR1C3 knockdown decreased YAP nuclear translocation, inhibited cystine transporter SLC7A11, increased intracellular ferrous iron, and induced ferroptosis; overexpression of AKR1C3 protected against ferroptosis. AKR1C3 knockdown and overexpression; YAP nuclear localization assay; SLC7A11 expression analysis; ferrous iron measurement; ferroptosis inducer sensitivity assays in vitro and in vivo Molecular carcinogenesis Medium 36920042
2023 AKR1C3 stabilizes AR in a non-enzymatic manner to induce FASN (fatty acid synthase) in PCOS adipocytes: insulin-induced AKR1C3 activates FASN through a PI3K/AKT/mTOR/NRF2 pathway in an AKR1C3- and AR-dependent manner; AKR1C3 interacts with AR (Co-IP, proximity ligation assay), co-occupies the FASN locus (ChIP-qPCR), and stabilizes AR from degradation; bifunctional but not monofunctional AKR1C3 inhibitors blocked FASN induction and lipid droplet formation. Co-immunoprecipitation; proximity ligation assay; ChIP-qPCR (AKR1C3 and AR co-occupancy at FASN promoter); pharmacological inhibition (PI3K/AKT/mTOR/NRF2 pathway); monofunctional vs. bifunctional inhibitor comparison; insulin treatment of SGBS adipocytes Endocrinology High 36799021
2023 Full-length androgen receptor (AR-FL) reciprocally regulates AKR1C3 expression by binding to a distal enhancer region of the AKR1C3 gene; PTUPB, a novel dual inhibitor, suppresses AKR1C3 activity more effectively than indomethacin or celecoxib, and synergizes with enzalutamide to suppress CRPC tumor growth by blocking AR/AR-V7 signaling. AR ChIP on AKR1C3 distal enhancer; AKR1C3 enzymatic activity assays; VCaP xenograft and patient-derived xenograft organoid experiments; combination drug treatment Oncogene Medium 36596844
2012 Activin A induces AKR1C3 expression and enzymatic activity (testosterone synthesis) in prostate cancer LNCaP and VCaP cells; inhibition of endogenous activin A in PC-3 cells decreased AKR1C3 levels and testosterone synthesis; androgens in turn suppress INHBA (activin A subunit) expression, forming a regulatory feedback. Activin A treatment and antagonist inhibition in prostate cancer cell lines and xenograft models; RT-PCR and protein expression; testosterone measurement; PC xenograft gene expression analysis Endocrinology Medium 23024260
2018 AKR1C3 promotes prostate cancer metastasis by activating ERK signaling to drive epithelial-mesenchymal transition (EMT): knockdown of AKR1C3 or inhibition of its enzymatic activity suppressed cell migration/invasion, increased E-cadherin, decreased vimentin, and downregulated ERK phosphorylation and EMT transcription factors (ZEB1, TWIST1, SLUG) in vitro; AKR1C3 knockdown also reversed EMT and suppressed tumor growth in xenografts. shRNA knockdown of AKR1C3; chemical inhibitor treatment; wound healing and Transwell invasion assays; Western blot for EMT markers and phospho-ERK; subcutaneous xenograft experiments; IHC on clinical specimens Urologic oncology Medium 30139661
2015 AKR1C3 is the critical enzyme activating the nitrogen mustard prodrug PR-104A: overexpression of AKR1C3 in resistant B-ALL xenografts dramatically sensitized tumors to PR-104 in vivo; AKR1C3 expression correlated with PR-104/PR-104A sensitivity across T-ALL and B-ALL xenografts and primary patient blasts. AKR1C3 overexpression by lentiviral transduction; patient-derived xenograft in vivo efficacy studies; in vitro cytotoxicity assays; AKR1C3 expression analysis Blood High 26116659
2015 11β-PGF2α, a metabolite catalyzed by AKR1C3 from PGD2, stimulates the FP (prostaglandin F) receptor, phosphorylates ERK and CREB, and induces Slug expression in breast cancer cells expressing FP receptor, decreasing chemosensitivity. AKR1C3 metabolite identification; FP receptor-overexpressing MCF-7 cells; 11β-PGF2α treatment; Western blot (ERK/CREB phosphorylation); gene expression (Slug); chemosensitivity assays; IHC correlation in clinical specimens Molecular and cellular endocrinology Medium 26170067

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer. Cancer research 220 25649766
2017 AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. The Journal of clinical endocrinology and metabolism 168 28645211
2003 The human DDX and DHX gene families of putative RNA helicases. Genomics 145 12782131
2004 Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. Carcinogenesis 142 15284179
2005 AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Molecular and cellular endocrinology 140 16338060
2013 AKR1C3 as a target in castrate resistant prostate cancer. The Journal of steroid biochemistry and molecular biology 117 23748150
2006 Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocrine-related cancer 115 16601286
2004 Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. BMC cancer 115 15212687
2013 Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clinical cancer research : an official journal of the American Association for Cancer Research 109 23995860
2016 Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer. Molecular cancer therapeutics 108 27794047
2009 Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. The Journal of clinical endocrinology and metabolism 102 19336506
2020 A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma. Cancer research 96 33361392
2018 AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders. Molecular and cellular endocrinology 94 30012349
2008 Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. Carcinogenesis 90 18632753
2001 Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Molecular and cellular endocrinology 88 11165022
2013 Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. Journal of medicinal chemistry 86 23432095
2019 Paralog Studies Augment Gene Discovery: DDX and DHX Genes. American journal of human genetics 77 31256877
2020 Overview of AKR1C3: Inhibitor Achievements and Disease Insights. Journal of medicinal chemistry 76 32463235
2020 Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer. Molecular cancer therapeutics 69 32430485
2015 ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells. Clinical cancer research : an official journal of the American Association for Cancer Research 64 25754347
2019 AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer. Molecular cancer therapeutics 63 31308078
2008 AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chemico-biological interactions 61 19007764
2014 The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chemico-biological interactions 56 25514466
2010 Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progression. BMC cancer 56 21134280
2012 Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. Bioorganic & medicinal chemistry letters 55 22507964
2016 Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation. Oncotarget 53 27385003
2014 Aldo-keto reductase 1C3 (AKR1C3) is associated with the doxorubicin resistance in human breast cancer via PTEN loss. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 52 25661377
2013 Distinct DDX DEAD-box RNA helicases cooperate to modulate the HIV-1 Rev function. Biochemical and biophysical research communications 52 23608157
2015 AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood 51 26116659
2022 Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes. Endocrinology 50 35560164
2022 AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy. Theranostics 50 36451864
2019 Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. Journal of medicinal chemistry 50 30836001
2013 Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2α-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD). Biology of reproduction 50 23677986
2018 AKR1C3, a crucial androgenic enzyme in prostate cancer, promotes epithelial-mesenchymal transition and metastasis through activating ERK signaling. Urologic oncology 49 30139661
2008 AKR1C2 and AKR1C3 mediated prostaglandin D2 metabolism augments the PI3K/Akt proliferative signaling pathway in human prostate cancer cells. Molecular and cellular endocrinology 49 18508192
2014 AKR1C3 overexpression may serve as a promising biomarker for prostate cancer progression. Diagnostic pathology 48 24571686
2013 Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis. PloS one 47 23437342
2015 Effect of insulin on AKR1C3 expression in female adipose tissue: in-vivo and in-vitro study of adipose androgen generation in polycystic ovary syndrome. Lancet (London, England) 46 26312838
2011 Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis. Chemico-biological interactions 46 21232532
2018 AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells. Molecular cancer therapeutics 44 29891491
2011 Proteasome inhibitors MG-132 and bortezomib induce AKR1C1, AKR1C3, AKR1B1, and AKR1B10 in human colon cancer cell lines SW-480 and HT-29. Chemico-biological interactions 43 21215737
2006 Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost. Biochemistry 43 16475787
2023 AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway. Molecular carcinogenesis 42 36920042
2014 Elevated expression of AKR1C3 increases resistance of cancer cells to ionizing radiation via modulation of oxidative stress. PloS one 42 25419901
2021 Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response. Environment international 40 34991250
2020 Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer. Journal of medicinal chemistry 40 32847363
2012 Activin A stimulates AKR1C3 expression and growth in human prostate cancer. Endocrinology 40 23024260
2014 Modification of Streptococcus mutans Cnm by PgfS contributes to adhesion, endothelial cell invasion, and virulence. Journal of bacteriology 39 24837294
2018 Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid. European journal of medicinal chemistry 38 29602039
2014 Expression of AKR1C3 and CNN3 as markers for detection of lymph node metastases in colorectal cancer. Clinical and experimental medicine 38 24934327
2006 Expression of cyclooxygenase-II (COX-II) and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD)/prostaglandin F-synthase (PGFS) in bovine placentomes: implications for the initiation of parturition in cattle. Placenta 38 16375967
2019 OBI-3424, a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T-ALL. Clinical cancer research : an official journal of the American Association for Cancer Research 37 31015346
2016 Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines. ACS medicinal chemistry letters 37 27563402
2014 Induction of aldo-keto reductases (AKR1C1 and AKR1C3) abolishes the efficacy of daunorubicin chemotherapy for leukemic U937 cells. Anti-cancer drugs 35 24743520
2010 Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3. Chemico-biological interactions 33 21182831
2020 Host DDX Helicases as Possible SARS-CoV-2 Proviral Factors: A Structural Overview of Their Hijacking Through Multiple Viral Proteins. Frontiers in chemistry 32 33381492
2015 The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells. The Journal of biological chemistry 32 26160177
2014 Expression of AKR1B1, AKR1C3 and other genes of prostaglandin F2α biosynthesis and action in ovarian endometriosis tissue and in model cell lines. Chemico-biological interactions 32 25446850
2012 Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma. International journal of clinical and experimental pathology 32 22670171
2024 DDX RNA helicases: key players in cellular homeostasis and innate antiviral immunity. Journal of virology 31 39212449
2021 Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death. International journal of molecular sciences 31 34830394
2017 Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach. European journal of medicinal chemistry 31 28881288
2008 The Caenorhabditis elegans DDX-23, a homolog of yeast splicing factor PRP28, is required for the sperm-oocyte switch and differentiation of various cell types. Developmental dynamics : an official publication of the American Association of Anatomists 31 18729217
2022 AKR1C3 regulated by NRF2/MAFG complex promotes proliferation via stabilizing PARP1 in hepatocellular carcinoma. Oncogene 30 35773412
2014 The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer. Frontiers in oncology 30 24995161
2007 Canine prostaglandin F2alpha receptor (FP) and prostaglandin F2alpha synthase (PGFS): molecular cloning and expression in the corpus luteum. Animal reproduction science 30 17689894
2015 11β-Prostaglandin F2α, a bioactive metabolite catalyzed by AKR1C3, stimulates prostaglandin F receptor and induces slug expression in breast cancer. Molecular and cellular endocrinology 29 26170067
2014 Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Chemico-biological interactions 29 25555457
2005 GABAA receptor-associated protein (GABARAP) induces apoptosis by interacting with DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47). Biotechnology letters 29 15977068
2010 Suppressed expression of type 2 3alpha/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma. International journal of clinical and experimental pathology 28 20661409
2008 Tissue distribution of human AKR1C3 and rat homolog in the adult genitourinary system. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 28 18574251
2019 Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells. Biochemical and biophysical research communications 27 31253396
2008 Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia. Carcinogenesis 27 18339682
2019 AKR1C3 expression in primary lesion rebiopsy at the time of metastatic castration-resistant prostate cancer is strongly associated with poor efficacy of abiraterone as a first-line therapy. The Prostate 26 31294486
2009 Expression of AKR1C3 in renal cell carcinoma, papillary urothelial carcinoma, and Wilms' tumor. International journal of clinical and experimental pathology 25 20126582
2013 Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3. European journal of medicinal chemistry 24 23454516
2024 AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies. Frontiers in pharmacology 22 38523637
2021 AKR1C2 and AKR1C3 expression in adipose tissue: Association with body fat distribution and regulatory variants. Molecular and cellular endocrinology 22 33675863
2020 The AKR1C3/AR-V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression. Journal of cellular and molecular medicine 22 32902124
2019 A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics. The Journal of steroid biochemistry and molecular biology 22 30641225
2018 Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile. Archives of toxicology 22 29992508
2014 Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors. The Journal of steroid biochemistry and molecular biology 22 24769118
2023 Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3. Food & nutrition research 21 36794010
2018 Expression of PTGS2, PGFS and PTGFR during downregulation and restart of spermatogenesis following GnRH agonist treatment in the dog. Cell and tissue research 21 30198052
2014 AKR1C3 overexpression mediates methotrexate resistance in choriocarcinoma cells. International journal of medical sciences 21 25170291
2022 Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer. European journal of medicinal chemistry 20 36566714
2021 AKR1C3 and Its Transcription Factor HOXB4 Are Promising Diagnostic Biomarkers for Acute Myocardial Infarction. Frontiers in cardiovascular medicine 20 34568444
2020 AKR1C3 Is Associated with Better Survival of Patients with Endometrial Carcinomas. Journal of clinical medicine 20 33352741
2022 The ADAM9/UBN2/AKR1C3 axis promotes resistance to androgen-deprivation in prostate cancer. American journal of cancer research 19 35141012
2015 A novel function for the DEAD-box RNA helicase DDX-23 in primary microRNA processing in Caenorhabditis elegans. Developmental biology 19 26601717
2016 Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. Biochemical pharmacology 18 27453434
2015 Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells. The Journal of steroid biochemistry and molecular biology 18 26429394
2012 Prostaglandin endoperoxide synthase 2 (PTGS2) and prostaglandins F2α and E2 synthases (PGFS and PGES) expression and prostaglandin F2α and E2 secretion following oestrogen and/or progesterone stimulation of the feline endometrium. Reproduction in domestic animals = Zuchthygiene 18 22583354
2023 Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer. Oncogene 17 36596844
2020 AKR1C3 is a biomarker and druggable target for oropharyngeal tumors. Cellular oncology (Dordrecht, Netherlands) 17 33211282
2008 Association of the 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) with hyperandrogenemia in polycystic ovary syndrome (PCOS). Fertility and sterility 17 18692800
2023 Insulin-Induced AKR1C3 Induces Fatty Acid Synthase in a Model of Human PCOS Adipocytes. Endocrinology 16 36799021
2007 Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche. The Journal of steroid biochemistry and molecular biology 16 17583494
2022 New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold. European journal of medicinal chemistry 15 35447434
2010 Polymorphisms of the HSD17B6 and HSD17B5 genes in Chinese women with polycystic ovary syndrome. Journal of women's health (2002) 14 21039282

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