Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated ...the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.
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•STK11/KEAP1 co-mutation promotes cell proliferation, independent of KRAS status•NRF2 activity is enhanced in STK11/KEAP1 co-mutation beyond KEAP1 loss alone•STK11 and KEAP1 mutations each independently promote ferroptosis protection•SCD1 protects STK11/KEAP1 co-mutant LUAD from ferroptosis and is essential for survival
Wohlhieter et al. explore the global changes in gene expression and oncogenic signaling pathways driven by concurrent loss of function in two tumor suppressor genes, STK11 and KEAP1. They identify a molecular vulnerability, in which co-mutant cells depend on ferroptosis protective mechanisms for survival, and highlight SCD1 as an essential gene and promising drug target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human aldo-keto reductase family 1C1 (AKR1C1) is an important enzyme involved in human hormone metabolism, which is mainly responsible for the metabolism of progesterone in the human body. AKR1C1 is ...highly expressed and has an important relationship with the occurrence and development of various diseases, especially some cancers related to hormone metabolism. Nowadays, many inhibitors against AKR1C1 have been discovered, including some synthetic compounds and natural products, which have certain inhibitory activity against AKR1C1 at the target level. Here we briefly reviewed the physiological and pathological functions of AKR1C1 and the relationship with the disease, and then summarized the development of AKR1C1 inhibitors, elucidated the interaction between inhibitors and AKR1C1 through molecular docking results and existing co-crystal structures. Finally, we discussed the design ideals of selective AKR1C1 inhibitors from the perspective of AKR1C1 structure, discussed the prospects of AKR1C1 in the treatment of human diseases in terms of biomarkers, pre-receptor regulation and single nucleotide polymorphisms, aiming to provide new ideas for drug research targeting AKR1C1.
•Detailed analysis that the structural features and functions of the AKR1Cs.•Detailed analysis that the relationship between AKR1C1 and diseases.•Summarize the research progress of AKR1C1 inhibitors.•Give insight into the design of AKR1C1 inhibitors for follow-up research.•Provide our insights on the prospects of AKR1C1 in disease treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and ...underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway.
•AKR1C1 accelerates the proliferation of NSCLC cells.•AKR1C1 remodels metabolism in NSCLC cells.•HIF-1α may play a vital role in AKR1C1-mediated metabolic reprogramming.
Non-small cell lung cancer ...(NSCLC) ranks first among cancer death worldwide. Despite efficacy and safety priority, targeted therapy only benefits ∼30% patients, leading to the unchanged survival rates for whole NSCLC patients. Metabolic reprogramming occurs to offer energy and intermediates for fuelling cancer cells proliferation. Thus, mechanistic insights into metabolic reprogramming may shed light upon NSCLC proliferation and find new proper targets for NSCLC treatment. Herein, we used loss- and gain-of-function experiments to uncover that highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerated NSCLC cells proliferation via metabolic reprogramming. Further molecular profiling analyses demonstrated that AKR1C1 augmented the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which could drive tumour metabolic reprogramming. What's more, AKR1C1 significantly correlated with HIF-1α signaling, which predicted poor prognosis for NSCLC patients. Collectively, our data display that AKR1C1 reprograms tumour metabolism to promote NSCLC cells proliferation by activating HIF-1α. These newly acquired data not only establish the specific role for AKR1C1 in metabolic reprogramming, but also hint to the possibility that AKR1C1 may be a new therapeutic target for NSCLC treatment.
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In non-small cell lung cancer (NSCLC) cells, highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerates proliferation of NSCLC cells involving in activation of hypoxia-inducible factor 1-alpha (HIF-1α) signalling, the latter of which could reprogram metabolism to fuel tumour proliferation. This study not only uncovers a novel role of AKR1C1 in metabolic reprogramming, but also highlights a possible target for AKR1C1-dominated NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths, characterized by high invasion and metastasis. Aldo-keto reductase family 1 member C1 (AKR1C1) plays an ...important role in cancer cell proliferation and metastasis, and has gained attention as an anticancer drug target. Here, we report that the natural sesquiterpene lactone alantolactone (ALA) was shown to bind directly to AKR1C1 through the Proteome Integral Solubility Alteration (PISA) analysis, a label-free target identification approach based on thermal proteome profiling. Acting as a specific inhibitor of AKR1C1, ALA selectively inhibits the activity of AKR1C1 and ALA treatment in human non-small-cell lung cancer (NSCLC) cell results in a reduction in cell proliferation and metastasis, inhibition of AKR1C1 expression, and deactivation of STAT3. Moreover, ALA inhibited tumor growth
, and the inhibition of AKR1C1 and STAT3 activation were also found in the murine xenograft model. Collectively, our work not only gives mechanistic insights to explain the bioactivity of ALA in anticancer but also provides opportunities of developing novel sesquiterpene lactone-based AKR1C1 inhibitors for the treatment of NSCLC.
Novel treatments for castration-resistant prostate cancer (CRPC) such as abiraterone acetate (AA) or enzalutamide effectively target the androgen pathway to arrest aberrant signalling and cell ...proliferation. Testosterone is able to inhibit tumour cell growth in CRPC. Estrogen receptor-beta (ERβ) binds the testosterone-metabolites 3β-androstanediol and 3α-androstanediol in parallel to the canonical estradiol. In the prostate it is widely accepted that ERβ regulates estrogen signalling, mediating anti-proliferative effects. We used the prostate cancer cell lines LNCaP, PC-3, VCaP, and the non-neoplastic BPH-1. VCaP cells were treated with 1 nmol/L testosterone over 20 passages, yielding the cell line VCaPrev, sensitive to hormone therapies. In contrast, LNCaP cells were grown for more than 100 passages yielding a high passage therapy resistant cell line (
LNCaP). VCaP and
LNCaP cell lines were treated with 5 μmol/L AA for more than 20 passages, respectively, generating the AA-tolerant-subtypes VCaP
and hiPLNCaP
. Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC.
The mechanism by which human labor is initiated in the presence of elevated circulating progesterone levels remains unknown. Recent evidence indicates that the progesterone-metabolizing enzyme, ...20α-hydroxysteroid dehydrogenase (20α-HSD), encoded by the gene
AKR1C1
, may contribute to functional progesterone withdrawal. We found that
AKR1C1
expression significantly increased with labor onset in term myometrium, but not in preterm myometrium. Among preterm laboring deliveries, clinically diagnosed chorioamnionitis was associated with significantly elevated
AKR1C1
expression.
AKR1C1
expression positively correlated with BMI before labor and negatively correlated with BMI during labor. Analysis by fetal sex showed that
AKR1C1
expression was significantly higher in women who delivered male babies compared to women who delivered female babies at term, but not preterm. Further, in pregnancies where the fetus was female,
AKR1C1
expression positively correlated with the mother’s age and BMI at the time of delivery. In conclusion, the increase in myometrial
AKR1C1
expression with term labor is consistent with 20α-HSD playing a role in local progesterone metabolism to promote birth. Interestingly, this role appears to be specific to term pregnancies where the fetus is male. Upregulated
AKR1C1
expression in the myometrium at preterm in-labor with clinical chorioamnionitis suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. The link between
AKR1C1
expression and maternal BMI may provide insight into why maternal obesity is often associated with dysfunctional labor. Higher myometrial
AKR1C1
expression in male pregnancies may indicate fetal sex-related differences in the mechanisms that precipitate labor onset at term.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Different studies have shown that HPV16‐positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). Because we showed that integration neither affects the ...levels of viral genes, nor those of virally disrupted human genes, a genome‐wide screen was performed to identify human genes which expression is influenced by viral integration and have clinical relevance. Thirty‐three fresh‐frozen HPV‐16 positive OPSCC samples with known integration status were analyzed by mRNA expression profiling. Among the genes of interest, Aldo‐keto‐reductases 1C1 and 1C3 (AKR1C1, AKR1C3) were upregulated in tumors with viral integration. Additionally, 141 OPSCC, including 48 HPV‐positive cases, were used to validate protein expression by immunohistochemistry. Results were correlated with clinical and histopathological data. Non‐hierarchical clustering resulted in two main groups differing in mRNA expression patterns, which interestingly corresponded with viral integration status. In OPSCC with integrated viral DNA, often metabolic pathways were deregulated with frequent upregulation of AKR1C1 and AKR1C3 transcripts. Survival analysis of 141 additionally immunostained OPSCC showed unfavorable survival rates for tumors with upregulation of AKR1C1 or AKR1C3 (both p <0.0001), both in HPV‐positive (p ≤0.001) and ‐negative (p ≤0.017) tumors. OPSCC with integrated HPV16 show upregulation of AKR1C1 and AKR1C3 expression, which strongly correlates with poor survival rates. Also in HPV‐negative tumors, upregulation of these proteins correlates with unfavorable outcome. Deregulated AKR1C expression has also been observed in other tumors, making these genes promising candidates to indicate prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.
What's new?
Oropharyngeal squamous cell carcinoma (OPSCC) is often associated with high‐risk human papillomavirus infection, especially HPV16, but the clinical relevance of viral integration in a subset of these tumors remains unclear. Here the authors describe transcriptional signatures of metabolic reprogramming including increased expression of the aldo‐keto‐reductases AKR1C1 and AKR1C3 proteins in OPSCC cells regardless of HPV status. Tumors with upregulation of these proteins were strongly associated with poor prognosis suggesting prognostic as well as therapeutic implications for OPSCC patients beyond HPV16 infection.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose: To investigate the involvement of aldo-keto reductase family 1 member C1 (AKR1C1) in glycyrrhizic acid-mediated gastric cancer.Methods: Immunohistochemistry, quantitative real-time reverse ...transcription polymerase chain reaction (qRT-PCR), and western blot were used to assess AKR1C1 expression in gastric cancer. Cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assay. Apoptosis was evaluated by flow cytometry. Transwell and wound healing assays were performed to investigate cell invasion and migration, respectively.Results: AKR1C1 was significantly upregulated in gastric cancer tissues and cells (p < 0.01). AKR1C1 knockdown suppressed cell proliferation, migration, and invasion of gastric cancer, but promoted cell apoptosis. Glycyrrhizic acid treatment reduced AKR1C1 expression in gastric cancer cells (p < 0.05). AKR1C1 overexpression attenuated the glycyrrhizic acid-induced increase in gastric cancer cell apoptosis as well as the decrease in cell proliferation, migration, and invasion.Conclusion: AKR1C1 contributes to gastric cancer cell proliferation and metastasis and counteracts the suppressive effects of glycyrrhizic acid on gastric cancer cell proliferation and metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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