Cyclooxygenase 2 (COX-2) overexpression is found in a wide variety of human cancers and is linked to all stages of tumorigenesis. Elevated tumor COX-2 expression is associated with increased angiogenesis, tumor invasion, suppression of host immunity and promotes tumor cell resistance to apoptosis. Previous reports have linked the COX-2 product prostaglandin E 2 (PGE 2 ) to the abnormal activation of the mitogen-activated protein kinase/Erk kinase pathway. Here we show that PGE 2 is able to rapidly stimulate Erk phosphorylation in a subset of non-small cell lung cancer (NSCLC) cell lines. This effect is not evident in bronchial epithelial cells. In contrast to previous reports in colon cancer, we found that Erk activation as well as cellular proliferation induced by PGE 2 was not inhibited by pretreatment of the cells with epidermal growth factor receptor (EGFR) inhibitors. Activation of the Erk pathway by PGE 2 was also resistant to src kinase inhibitors but sensitive to the protein kinase C inhibition. PGE 2 effects are mediated through four G protein-coupled receptors. Selective inhibition of EP receptors revealed the possible involvement of Ca 2+ -dependent signaling in PGE 2 -mediated activation of Erk. Our data indicate the presence of an EGFR-independent activation of the mitogen-activated protein kinase/Erk pathway by PGE 2 in NSCLC cells. These findings provide evidence for the possible link between tumor COX-2 overexpression and elevated Erk-mediated cancer cell proliferation and migration. Importantly, these findings suggest that COX-2 overexpression may contribute to EGFR inhibitor resistance in NSCLC. (Cancer Res 2005; 65(14): 6275-81)

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Commensal bacteria have emerged as an important disease factor in human Crohn's disease (CD) and murine inflammatory bowel disease (IBD) models. We recently isolated I2, a novel gene segment of microbial origin that is associated with human CD and that encodes a T-cell superantigen. To identify the I2 microorganism, BLAST analysis was used to identify a microbial homologue, PA2885, a novel open reading frame (ORF) in the Pseudomonas aeruginosa genome. PCR and Southern analysis identified Pseudomonas fluorescens as the originating species of I2, with homologues detectable in 3 of 13 other Pseudomonas species. Genomic cloning disclosed a locus containing the full-length I2 gene (pfiT) and three other orthologous genes, including a homologue of the pbrA/pvdS iron response gene. CD4؉ T-cell responses to recombinant proteins were potent for I2 and pfiT, but modest for PA2885. pfiT has several features of a virulence factor: association with an iron-response locus, restricted species distribution, and T-cell superantigen bioactivity. These findings suggest roles for pfiT and P. fluorescens in the pathogenesis of Crohn's disease.Human inflammatory bowel disease (IBD) represents a set of a chronic, relapsing, and remitting intestinal inflammatory disorders involving T-cell-mediated mucosal and mural destruction, with polygenic disease susceptibility (4, 13, 38). Although the etiology of these diseases remains uncertain, several lines of evidence implicate commensal bacteria as an important pathogenic element in clinical disease, particularly in Crohn's disease (CD). Patients with CD are sensitive to alteration of fecal flow, and some investigators have reported evidence of a clinical responsiveness to antibiotic therapy (21,24,34). In both pharmacologic and genetic animal models of IBD, development of disease is strictly dependent on the presence of enteric microflora (19,29,(35)(36)(37)40).The identity of colitigenic bacterial species remains uncertain. In humans, a variety of bacterial and viral species have been implicated in CD, mainly on the basis of seroreactivity (3,5,8,28,44). However, CD patients typically express elevated levels of antibodies to many bacterial proteins, perhaps due to mucosal disruption and local immunologic challenge by diverse intestinal microflora. Mycobacterium has received attention as a candidate human pathogen, based on serologic evidence, but the presence of mycobacterial DNA in lesions is controversial (9,12,31,32,43,47). Bacteroides vulgatus and Helicobacter hepaticus have been evaluated with various rodent IBD models, but other intestinal commensal organisms yet undefined are likely to account for the major colitigenic species (14,25,35,36).Our laboratory recently introduced subtractive cloning as a fresh approach to identify candidate organisms in human CD (10, 45). A novel microbial gene, I2, was isolated from lesional versus adjacent uninvolved colon tissues of a patient with CD. In a population-based study (45), the I2 gene was selectively detected in lesional CD colonic tissue,...

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