Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2

BackgroundEpidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion.MethodsFusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting.ResultsOur data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events.ConclusionThese novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression

Hydrogen peroxide stimulates glucose uptake in myotube cells via the insulin signaling pathway

Recent studies suggest that reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) may exert beneficial effects on health. Therefore this study evaluated the effects of H2O2 and gamma-tocotrienol (GTT), an antioxidant, on D-[2-3H]Glucose uptake by myotubes compared to insulin. Results showed that H2O2 and insulin significantly increased D-[2-3H]Glucose uptake. This was associated with an increased in Vmax but Michaelis constant (Km) of the transport system remained unchanged indicating that an increase in amount, rather than affinity, of the glucose transporter was involved in the process. Western blot studies confirmed that H2O2 increased the expressions of insulin sensitive glucose transporter, GLUT4 and also hexokinase (an enzyme which phosphorylates glucose and indirectly stimulates glucose uptake by cells). H2O2 and insulin also stimulated increased in PPAR-γ and IRS-1, which are proteins of the insulin transduction pathway. The present data however showed that GTT did not exert any effect on glucose uptake. Thus, the study showed that H2O2 mimicked insulin action in stimulating glucose uptake in myotube cells by influencing the insulin signaling pathway