title: N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression.
abstract: N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-kappaB (NF-kappaB) signaling attenuation through marked decreases in inhibitor of kappaB kinase (IKK) beta expression and IkappaBalpha phosphorylation. Decreased IKKbeta expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-kappaB motif. The introduction of an exogenous IKKbeta gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity alpha/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IkappaBalpha in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-kappaB signaling.
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Hosoi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D018925:Chemokines; D017931:DNA Primers; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein