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...

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