Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells

Doig, Craig; Battaglia, Sebastiano; Khanim, Farhat L.; Bunce, Christopher M.; Campbell, Moray J.

doi:10.1016/j.jsbmb.2015.09.037

Cited by 19 publications

(7 citation statements)

References 66 publications

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“…Knockdown of AKR1C3 was accompanied by a significantly reduced expression of a range of histone deacetylases, transcriptional co-regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor. [85] Looking beyond PCa, UGT2B17 has been identified as a disease accelerator in chronic lymphocytic leukemia [86], and knockdown of UGT2B17 in an endometrial carcinoma cell line resulted in an increase in apoptosis in association with downregulation of the anti-apoptotic protein Mcl-1, and upregulation of the pro-apoptotic target of Mcl-1, Puma [87]. While the mechanism of UGT2B17 involvement in these tumors remains to be elucidated, these reports underscore the potential role of these enzymes in non-steroid metabolizing capacities.…”

Section: A Non-classical Role For Dht Metabolizing Enzymesmentioning

confidence: 99%

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Zhang

Plymate

et al. 2016

HORM CANC

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Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10 and the UGT family members UGT2B15 and UGT2B17, in controlling intra-tumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

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Section: A Non-classical Role For Dht Metabolizing Enzymesmentioning

confidence: 99%

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Zhang

Plymate

et al. 2016

HORM CANC

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“…As reported, AKR1C3 is a multifunctional enzyme that catalyzes multiple hormones and xenobiotic metabolism (Dufort et al, 1996; Matsuura et al, 1998). A growing number of studies have shown that overexpressed AKR1C3 occurs in multiple types of human cancer and is involved in the development of human cancer and chemotherapy resistance, such as hepatocellular carcinoma, prostate cancer, breast cancer and esophageal cancer (Doig et al, 2016; Li, 2018a; Pan et al, 2022; Xu et al, 2017). More intriguingly, AKR1C3 exhibits elevated expression in thyroid cancer tissues, and high AKR1C3 expression tends to have a poor prognosis (Wang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

AKR1C3 silencing inhibits autophagy‐dependent glycolysis in thyroid cancer cells by inactivating ERK signaling

Gao,

Tao,

Wang

et al. 2024

Drug Development Research

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Thyroid cancer is a highly differentiated and poorly malignant tumor. Interfering with glycolysis has become an effective means of controlling cancer progression and autophagy is negatively correlated with glycolysis. Aldo‐keto reductase family 1 member C3 (AKR1C3) has been demonstrated to be highly expressed in thyroid cancer tissue and the higher AKR1C3 expression predicted the worse prognosis. We aimed to explore whether AKR1C3 could affect thyroid cancer progression by regulating autophagy‐dependent glycolysis. AKR1C3 expression in thyroid cancer cells was detected by western blot. Then, AKR1C3 was knocked down by transfection with short hairpin RNA specific to AKR1C3 in the absence or presence of 3‐methyladenine (3‐MA) or PMA treatment. Cell cycle and apoptosis was detected by flow cytometry. Immunofluorescence staining was used to analyze LC3B expression. Extracellular acidification, glucose uptake and lactic acid secretion were detected. To evaluate the tumorigenicity of AKR1C3 insufficiency on thyroid cancer in vivo, TPC‐1 cells with AKR1C3 knockdown were injected subcutaneously into nude mice. Then, cyclinD1 and Ki67 expression in tumorous tissues was measured by immunohistochemical analysis. Apoptosis was assessed by terminal‐deoxynucleoitidyl transferase mediated nick end labeling staining. Additionally, the expression of proteins related to cell cycle, apoptosis, glycolysis, autophagy, and extracellular signal‐regulated kinase (ERK) signaling in cells and tumor tissues was assessed by western blot. Highly expressed AKR1C3 was observed in thyroid cancer cells. AKR1C3 knockdown induced cell cycle arrest and apoptosis of TPC‐1 cells. Besides, autophagy was activated and glycolysis was inhibited following AKR1C3 silencing, and 3‐MA treatment restored the impacts of AKR1C3 silencing on glycolysis. The further experiments revealed that AKR1C3 insufficiency inhibited ERK signaling and PMA application reversed AKR1C3 silencing‐induced autophagy in TPC‐1 cells. The in vivo results suggested that AKR1C3 knockdown inhibited the development of subcutaneous TPC‐1 tumors in nude mice and inactivated the ERK signaling. Collectively, AKR1C3 silencing inhibited autophagy‐dependent glycolysis in thyroid cancer by inactivating ERK signaling.

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“…Interestingly, as previous studies stated, AKR1C1 could mediate the invasive potential and drug resistance of metastatic bladder cancer cells, and AKR1C1 was highly expressed in metastatic lesions of human bladder cancer patients 29 . AKR1C3, comes from the same family as AKR1C1, has not been proved to have similar functions as AKR1C1 in bladder cancer, but it is often overexpressed in prostate cancer tissues and prostate cancer cell lines 30 . AKR1C3 catalyzes the formation of prostaglandin (PG) F2α and 11β-PGF2α from PGH2 and PGD2, respectively 31 .…”

Section: Discussionmentioning

confidence: 99%

Effects and mechanisms of AMIGO2 in proliferation, migration and drug resistance of bladder cancer

Han

Xiong

Zhang

et al. 2020

Preprint

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Background Bladder cancer is the most common malignancy in urinary system, but the therapeutic targets remain elusive. This study aims to reveal the relationship between AMIGO2 and proliferation, migration, drug-resistance and tumorigenicity of bladder cancer, and explore the potential molecular mechanisms. Methods The expression of AMIGO2 in human bladder cancer tissues is measured by qRT-PCR and immunohistochemistry (IHC). Stable AMIGO2 knockdown cell lines T24 and 5637 were established by lentivirus transfection. Cell viability assay (CCK-8 assay) was used to determine cell proliferation, flow cytometry analysis was utilized to detect cell cycle, and wound healing assay was proceeded to test migration ability of bladder cancer cells. Chemosensitivity to cisplatin was measured by CCK-8 assay. Xenograft mouse model was established for investigating the effect of AMIGO2 on tumor formation in vivo. The RNA Sequencing technology was used to explore differentially expressed genes (DEGs) between knockdown group and negative control group of T24. Bioinformatics analysis upon the results of RNA-Seq was proceeded to understand underlying mechanisms. Results AMIGO2 was upregulated in bladder cancer cells and tissues. Inhibited expression of AMIGO2 suppresses cell proliferation and migration, which might be mediated by cell cycle arrest in G1 phase. AMIGO2 could reduce chemoresistance to cisplatin in bladder cancer cells. Low AMIGO2 expression inhibited tumorigenicity of T24 in nude mice. 917 DEGs were identified by RNA-Sequencing technology and bioinformatics analysis. The DEGs were mainly enriched in cell-cell adhesion, ATP-binding cassette transporters (ABC transporters), PPAR signaling pathway and some other pathways. Among ten hub genes, four of them might be associated with the prognosis of bladder cancer patients. Conclusion AMIGO2 is overexpressed in bladder cancer cells and tissues and serves as an oncogene in bladder cancer. It also reduces chemoresistance to cisplatin. The process might be regulated by particular pathways including ABC transporters and PPAR signaling pathway. Four hub genes might be associated with prognosis of bladder cancer patients.

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Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells

Cited by 19 publications

References 66 publications

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

AKR1C3 silencing inhibits autophagy‐dependent glycolysis in thyroid cancer cells by inactivating ERK signaling

Effects and mechanisms of AMIGO2 in proliferation, migration and drug resistance of bladder cancer

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