casein-kinase-ii and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is a very common cause of hospitalization and surgery is currently the most effective therapy. MAP kinases (MAPKs) are a group of protein kinases with an important function in integrating physiological and pathological stimuli that might impact on cellular growth, differentiation and programmed cell death (apoptosis). Certain components of the MAPK signal-transduction pathways are involved in stimulus-specific fine-tuning of the activities mediated by the various MAPK families. As homeostasis is impaired in the hyperplastic prostate, aberrant coordination of the MAPK cascades might be implicated in a proliferative-apoptotic imbalance. Here, we hypothesize that the pathogenesis of BPH might be facilitated by functional anomalies in the MAPK circuitry and postulate that pharmacological 'rewiring' of MAPK pathways offers a potentially exciting new avenue for improved therapeutic control of clinical BPH.

Topics: Animals; Apoptosis; Casein Kinase II; Cell Cycle Proteins; Drug Design; Dual Specificity Phosphatase 1; Enzyme Inhibitors; Humans; Immediate-Early Proteins; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Phosphoprotein Phosphatases; Prostatic Hyperplasia; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Protein Tyrosine Phosphatases

Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease.

Topics: Casein Kinase II; Cell Nucleus; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Male; Neoplasm Proteins; Prostatic Hyperplasia; Prostatic Neoplasms; Transcription Factor RelA

Expression of the early growth response gene-1 (EGR-1) is elevated in prostate cancer and correlates with tumor progression. This study provides insight into the mechanism(s) that regulate EGR-1 expression and activity in malignant and benign prostate cells.. Western blotting and in vitro pulse labeling were used to examine EGR-1 protein levels and half-life in malignant (PC-3) and benign (BPH-1) prostate cell lines. EGR-1 functional ability was assessed by transient transfections with an EGR-1 promoter driven luciferase plasmid and electromobility shift assays (EMSAs) to assess DNA binding of the EGR-1 protein. Protein levels of casein kinase II (CKII) were evaluated by Western blotting.. PC-3 cells maintain high steady-state levels of EGR-1 protein, in part due to a longer half-life of EGR-1 protein. BPH-1 cells responded to mitogenic stimuli with increased EGR-1 protein levels, and enhanced transcriptional activity. In contrast, PC-3 cells showed no response to stimuli. DNA binding of EGR-1 was higher in BPH-1 cells than in PC-3 cells. This appears to be related to the heavily phosphorylated state of EGR-1 in PC-3 cells which is correlated with increased levels of CKII found in these cells.. PC-3 cells maintain a long lasting, heavily phosphorylated pool of EGR-1, which binds poorly to DNA and responds poorly to mitogenic stimulus. BPH-1 cells, in contrast, maintain a more responsive, less phosphorylated EGR-1 pool. These findings suggest that EGR-1 expression and activity is differentially regulated in PC-3 and BPH-1 cell lines.

Topics: Blotting, Western; Casein Kinase II; Cell Line, Tumor; DNA-Binding Proteins; DNA, Neoplasm; Early Growth Response Protein 1; Electrophoretic Mobility Shift Assay; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; In Situ Hybridization, Fluorescence; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Transcription Factors; Transcription, Genetic; Transfection