IL-8 produced by prostate cancer cells may be responsible for the androgen-independent growth of advanced prostate cancers. Accumulating evidence from microarray analyses and animal genetic models highlights the central involvement of the transcription factor early growth response-1 (EGR-1) in prostate carcinoma progression. It is unknown, however, whether knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated tumor metastasis. Here we show that EGR-1 knockdown by a specific shRNA-Egr1 inhibited gene transcription and production of IL-8 by the human prostate cancer cell line DU145. Conversely, enforced expression of EGR-1 in EGR-1-lacking PC3 prostate cancer cells markedly enhanced IL-8 transcription and secretion. By using wild type and a series of mutant IL-8 promoter luciferase constructs, we found that the NF-B binding site is important for EGR-1 regulation of IL-8. Furthermore, silencing EGR-1 suppressed a synergistically functional interaction between EGR-1 and NF-B. Consequently, knockdown of EGR-1 inhibited IL-8-mediated tumor colony formation and invasion. Thus, targeted knockdown of EGR-1 could be an effective therapeutic approach against prostate cancer.Prostate cancer is currently the most prevalent noncutaneous cancer in men in the Western world and is the second leading cause of male death from cancer. There is considerable evidence from experimental models and studies conducted on patient samples to support a role for the pro-inflammatory chemokine interleukin 8 (IL-8) 2 in the promotion of prostate cancer progression (1, 2). Several studies have now confirmed elevated expression of IL-8 and its associated receptors in prostate cancer (3-6), although these independent studies suggest markedly different distribution patterns for IL-8 and its receptors. By using immunohistochemistry staining, IL-8 expression was detected in glandular epithelial cells of prostate cancer tissue, with little or no IL-8 staining hypertrophy or normal prostate epithelium (7,8). In contrast, Huang et al., reported that IL-8 was expressed solely by neuroendocrine rather than epithelial cells. Their analysis of benign and malignant prostate tissue cores confirmed an increased IL-8 expression that correlated with progressive disease (9). These studies suggested that there is a consistent trend of increased and concurrent expression of IL-8 and its two receptors in prostate cancer tissue; thus, indicating that prostate cancer cells are subject to a continuous autocrine/paracrine stimulus. In addition, several studies have reported the detection of increased IL-8 levels in the serum of patients with either localized or metastatic prostate cancer relative to control patients or patients with benign prostatic hypertrophy (10, 11). It is evident that future research providing a more comprehensive understanding of the transcriptional, translational, and post-translational signaling basis for IL-8-promoted cell motility and cell invasion will be required to identify viable and effective therapeutic strategies to attenuate th...
Transcription factor E2F1 has been implicated in both apoptosis-promoting and apoptosis-suppressing effects. However, factors that mediate its antiapoptotic effects are still not identified. Using prostate tumor-derived cell lines, we showed here that E2F1 activated the expression of transcription factor EGR1 for promoting cell survival. E2F1 up-regulated the production of EGR1-induced growth factors, epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor II, which in turn activated the phosphoinositide-3-kinase/Akt pathway to resist drug-induced apoptosis. Moreover, E2F1 directly induced the transcription of the Egr1 gene using the KB site located in its proximal promoter. E2F1 physically interacted with the RelA subunit of nuclear factor-KB and modulated its transactivity to fully activate EGR1 transcription. Together, these studies uncovered a novel mechanism for E2F1-induced suppression of apoptosis in prostate cancer.
Transcription factor E2F1 has been largely studied as a promoter of S-phase transition in the cell cycle and as a regulator of apoptosis. Recently, E2F1 has been shown to regulate a wide range of genes in response to inflammatory stimulation of macrophages and to contribute to T cell activation in response to pathogens, implicating an extensive immunological role for E2F1. Dendritic cells (DCs) play critical roles as professional APCs in the development of immune responses. However, it is unclear whether E2F1 has any effect on DC phenotype or function. In this paper, we report that E2F1 acts as a suppressor of DC maturation. The level of E2F1 expression was transiently downregulated in the course of LPS-induced maturation of both human monocyte-derived DCs and a mouse DC cell line, DC2.4. Knockdown of E2F1 by small interfering RNA in DC2.4 cells resulted in both phenotypic and functional maturation, even without LPS treatment. Conversely, ectopic overexpression of E2F1 suppressed LPS-induced maturation of DC2.4 cells. Furthermore, knockdown of E2F1 caused the activation of several major signaling pathways known to be activated in the course of DC maturation, including Erk1/2, NF-κB, and PI3K/Akt, suggesting that E2F1 may be involved in regulating multiple signaling pathways in DCs. Finally, the alteration of phenotypic maturation by E2F1 was confirmed with bone marrow-derived DCs from E2F1 knockout mice. Overall, our data demonstrate for the first time that E2F1 is a critical regulator of DC maturation.
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