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

Zeng, Chenming; Chang, Ling‐Sai; Ying, Meidan; Cao, Ji; He, Qiaojun; Zhu, Hong; Yang, Bo

doi:10.3389/fphar.2017.00119

Cited by 99 publications

(100 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several high‐throughput screening campaigns have identified novel chemical matter that is more potent and selective for AKR1C3 as well as more tolerable than indomethacin 26‐29 . AKR1C3 is a multifunctional enzyme with catalytic‐dependent and independent functions that drive AR signaling activity 20,30 . Additional studies will be needed to determine whether the AKR1C3 functions in JNJ‐pan‐AR resistant prostate cancer are catalytically dependent, independent, or both.…”

Section: Discussionmentioning

confidence: 99%

AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

et al. 2020

View full text Add to dashboard Cite

Background Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration‐resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to these therapies within 2 years. JNJ‐pan‐AR is a broad‐spectrum AR antagonist that inhibits wild‐type AR as well as several mutated versions of AR that have emerged in patients on chronic antiandrogen treatment. In this work, we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ‐pan‐AR treatment. Methods The LNCaP JNJR prostate cancer subline was developed by chronically exposing LNCaP parental cells to JNJ‐pan‐AR. Transcriptomic and proteomic profiling was performed to identify potential drivers and/or biomarkers of the resistant phenotype. Results Several enzymes critical to intratumoral androgen biosynthesis, Aldo‐keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17 were identified as potential upstream regulators of the JNJ‐pan‐AR resistant cells. While we confirmed the overexpression of all three enzymes in the resistant cells only AKR1C3 expression played a functional role in driving JNJ‐pan‐AR resistance. We also discovered that AKR1C3 regulates UGT2B15 and UGT2B17 expression in JNJ‐pan‐AR resistant cells. Conclusions This study supports the rationale to further investigate the benefits of AKR1C3 inhibition in combination with antiandrogens to prevent CRPC disease progression.

show abstract

Section: Discussionmentioning

confidence: 99%

AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…17,42,43 Potential treatment options addressing oxidative stress related pathways involving NRF2, AKR1C and PI3K upregulation were recently discussed. [44][45][46] However, due to the high expression of AKR1C enzymes in normal tissues like liver and pancreas, it will be important to investigate potential adverse events of these drugs in these tissues.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV‐negative tumors is an indicator of poor prognosis

Huebbers

Verhees

Poluschkin

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

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.

show abstract

“…Testosterone and DHT concentrations are also determined by their inactivation and subsequent degradation (13,14,16). Analysis of the enzyme AKR1D1, which is responsible for converting progesterone, 17OH-progesterone, androstenedione and testosterone into inactive metabolites (13), revealed that its expression was increased in ZEB1-silenced cells, which may result in a greater inactivation of these hormone metabolites; however, the concentration of testosterone was increased in ZEB1-silenced cells.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the enzyme AKR1C2, which participates in the inactivation of DHT, was analyzed (14). The results revealed that ZEB1 silencing resulted in an increase in the mRNA and protein expression levels of AKR1C2 compared with in the corresponding controls ( Fig.…”

Section: Mrna and Protein Expression And Cellular Localization Of Thmentioning

confidence: 96%

Silencing of the transcriptional factor ZEB1 alters the steroidogenic pathway, and increases the concentration of testosterone and DHT in DU145 cells

et al. 2018

View full text Add to dashboard Cite

Prostate cancer (PCa) is the second most common type of male malignancy worldwide. The transcription factor zinc finger E-box binding homeobox 1 (ZEB1) is associated with epithelial-mesenchymal transition and is also involved in regulation of androgen receptor (AR) expression, the main ligands of which are testosterone and dihydrotestosterone (DHT). These androgens are synthesized through the steroidogenic pathway within the prostate, and their synthesis is altered in PCa. The present study aimed to determine the ZEB1-induced alterations in androgen synthesis and AR expression in the DU145 PCa cell line. Reverse transcription-quantitative polymerase chain reaction, western blotting and immunocytochemistry were used to determine the mRNA and protein expression levels, and cellular localization of steroidogenic pathway enzymes in the DU145 cell line in response to ZEB1 silencing. Furthermore, the concentrations of testosterone and DHT were detected in cell culture medium using ELISA. ZEB1-silenced cells exhibited an increase in testosterone and DHT production, an increase in AR expression and an alteration in the steroidogenic pathway. In particular, steroidogenic acute regulatory protein and 5α-reductase 2 expression levels were decreased, whereas cytochrome P450 family 17 subfamily A member 1, 5α-reductase 1, aldo-keto reductase family 1 member D1 and aldo-keto reductase family 1 member C2 expression levels were increased. In conclusion, the present study provided novel information regarding the regulation of intratumoral androgen production in PCa, which is relevant for the progression of the disease to a castration-resistant form.

show abstract

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

Cited by 99 publications

References 89 publications

AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV‐negative tumors is an indicator of poor prognosis

Silencing of the transcriptional factor ZEB1 alters the steroidogenic pathway, and increases the concentration of testosterone and DHT in DU145 cells

Contact Info

Product

Resources

About