Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest.

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.

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases (MMPs) and CC chemokine ligands (CCLs) were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of MMPs and CCLs, which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (PCNA). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase MMP and CCL gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.

Background and aims: Epidemiologically, type-2 diabetes mellitus (T2D) is associated with various cancer types. The factors linking these diseases are not understood yet. Since plasma FGF21 levels are increased in metabolic diseases, we asked whether FGF21 promotes tumor cell proliferation. Methods: Breast adenocarcinoma- (MCF7), prostate adenocarcinoma- (PC3), hepatocellular carcinoma- (HepG2) and, for control, non-transformed breast epithelial (MCF10a) cells were treated with recombinant human FGF21 (rhFGF21). Cell viability/cell number, DNA content, cellular protein and RNA were analyzed. Results: Treatment of MCF7, PC3, and MCF10a cells with increasing concentrations of rhFGF21 induced a modest but significant increase in cell viability/cell number (p < 0.001, p < 0.01 and p < 0.05), measured by XTT assay. No effect was seen in HepG2 cells. DNA amount was significantly increased in all cell lines. All cell lines expressed FGFR1, FGFR4 and FRS2 encoding surface receptors/receptor substrates involved in FGF21 signaling. A clear dose-response was seen in PC3 cells. In these cells, acute stimulation with rhFGF21 induced ERK1/2 phosphorylation. The expression of immediate early genes (FOS, JUN) and of IRS1 was significantly elevated within 4h. Furthermore, a trend for increase in SLC2A1 and HK2 expression was observed within 24h of rhFGF21 treatment. Conclusions: Our data show that FGF21 treatment of human carcinoma cells increases cell viability and proliferation probably via the MAPK pathway and induction of mitogenic and trophic genes. Thus, the hepatokine FGF21 elevated in metabolic diseases may represent a contributor to T2D-related tumor progression.