Search

Background: We have previously reported that ErbB family members regulate the signaling pathway leading to Akt and NF-kappaB activation in prostate cancer cells. In this study, the regulation of Akt2 expression in LNCaP, DU145, and PC-3 prostate cancer cell lines was investigated., Methods: Akt-2 expression was analyzed by western-blotting and Q-PCR in cell lines. We also analyzed the Akt-2 protein expression in a tissue microarray from 64 prostate cancer patients. Akt-2 promoter activity was assessed and analyzed by luciferase assay., Results: A concomitant over-expression of Her-2 and Akt2 expression was observed by western-blotting and quantitative-PCR in prostate cancer cell lines. A significant correlation between Her-2 and Akt2 protein expression was also observed by immunohistochemistry assay on prostate cancer tissues. In LNCaP cells, over-expression of Akt2 protein and mRNA was decreased by Her-2 pharmacologic inhibitors as well as small interfering RNA (siRNA) specific to Her-2. Cloning of the AKT2 promoter in a luciferase reporter plasmid further showed that Akt2 over-expression in cell lines is associated with increased AKT2 promoter activity suggesting that Her-2 modulates a signaling pathway involving AKT2 gene regulation., Conclusion: This study reveals a novel mechanism of Akt2 regulation in prostate cancer cells., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that Ikappa-B kinase-epsilon (IKKepsilon/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6., Results: In this study, we report that over-expression of IKKepsilon in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKKepsilon knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKKepsilon over-expression does not induce the activation of the IKKepsilon classical targets NF-kappaB and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKKepsilon expression results in its nuclear translocation, a phenomena that is TBK1-independent., Conclusions: This study identifies IKKepsilon as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer., (2009 Wiley-Liss, Inc.)

Background: Inositol hexakisphosphate (IP6) is a phytochemical exhibiting anticancer activity. Because few prostate cancer (PCa) cell lines have been used to study IP6, we assessed its efficacy in a panel of PCa cell lines., Methods and Results: Using WST-1 assays we observed that, although androgens did not modulate its efficacy, IP6 was more active in androgen receptor (AR) negative cells than in AR-positive cells. Stable expression of the AR in PC3 cells (PC3(AR)) decreased the response to IP6, which was reversed by an AR-targeting siRNA. Furthermore, AR expression in PC3 cells resulted in significantly reduced caspase-3 activation (P < 0.001) and DNA fragmentation (P < 0.05) in response to IP6. Similarly, although treatment with IP6 caused the upregulation of NF-kappaB-responsive (IkappaB-alpha, IRF-2) and p53/E2F-responsive genes (Puma, Noxa) in PC3 cells, this increase was reduced in PC3AR cells (P < 0.01)., Conclusion: We conclude that resistance to IP6 can be linked to a ligand-independent AR function., ((c) 2006 Wiley-Liss, Inc.)

Background: Recent research has highlighted the potential role of EGFR and Her-2 in the constitutive activation of NF-kappaB (NF-kappaB) in prostate cancer cells, although the mechanism by which these receptors activate NF-kappaB in these cells remains unclear., Methods and Results: Using pharmacological and genetic approaches we show that in PC-3 cells, EGFR and Her-2 are involved in the constitutive activation of NF-kappaB through two different mechanisms. EGFR activates NF-kappaB through the PI3K/Akt pathway that leads to the phosphorylation of IkappaBalpha on serines 32 and 36, thereby promoting the nuclear translocation of the p65 subunit. In contrast, Her-2 activates NF-kappaB through Casein Kinase II (CK-2) activation independently of IkappaBalpha phosphorylation on serines 32 and 36., Conclusions: Our study not only directly clarifies the signaling pathways involved in NF-kappaB activation in prostate cancer cell lines and but also provides a framework for further studies in the clinical characterization and management of prostate cancer., (Copyright (c) 2005 Wiley-Liss, Inc.)

Background: The mechanism through which NF-kappaB (NF-kappaB) is constitutively activated in prostate cancer cells remains unclear. We investigated whether members of the ErbB family of epidermal growth factor receptors (EGFR) are involved in the constitutive activation of NF-kappaB in prostate cancer cell lines., Methods and Results: EGFR, Her-2, and ErbB3 are expressed and constitutively activated in PC-3, DU145, and LNCaP prostate cancer cells lines. Using several pharmacological ErbB inhibitors, we demonstrate that EGFR and Her-2 are involved in the constitutive activation of NF-kappaB in PC-3 cells through two different mechanisms. EGFR activates NF-kappaB through the phosphorylation of IkappaBalpha on serines 32/36 thereby influencing the nuclear translocation of the p65 subunit. In contrast, Her-2 activates NF-kappaB independently of IkappaBalpha phosphorylation on serines 32/36., Conclusion: This study directly implicates ErbB receptors in the activation of NF-kappaB in PC-3 prostate cancer cells., (Copyright 2005 Wiley-Liss, Inc.)