Abstract
Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on AKR1 gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, AKR1C1 and AKR1C2 transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of AKR1C1, C2, and C3. Furthermore, both in human tissue and in PC3 cells, the transcript levels of AKR1C1, C2, and C3 showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of AKR1C1, C2, and C3. The higher transcript level of AKR1C was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis.
Highlights
Patients with type 2 diabetes (T2D) have a high risk of developing diabetes-driven complications, including retinopathy, neuropathy, and nephropathy [1]
Since aldo-keto reductase (AKR) family members have been reported to be major players in diabetic complications [4], we aimed to test whether these proteins are involved in prostate cancer (PCa) progression in patients with T2D
The gene expression levels of AKR1B1, which plays a key role in hyperglycemia-induced diabetic complications [2], remained unchanged in prostate samples of patients with T2D
Summary
Patients with type 2 diabetes (T2D) have a high risk of developing diabetes-driven complications, including retinopathy, neuropathy, and nephropathy [1]. The aldo-keto reductase (AKR) superfamily is one of the most promising drug targets for alleviating diabetic complications [2]. The human AKR superfamily consists of 13 multifunctional AKR proteins, all of which are NAD(P)(H)-dependent oxidoreductases [3]. These enzymes are involved in phase 1 metabolism of carbonyl substrates, including sugars, keto-steroids, and keto-prostaglandins [4]. Hyperglycemia results in elevated intracellular sorbitol and fructose contents; these evoke osmotic stress and subsequent tissue damage [4]. The application of AKR1B1 inhibitors could prevent or delay hyperglycemia-induced pathologies such as nephropathy, neuropathy, and retinopathy [2]. Applications of AKR1B1 inhibitors were, reported to attenuate both pathways [4]
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