This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-4882v1 69/12/4983    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hosoi, F. Articles by Ono, M. PubMed PubMed Citation Articles by Hosoi, F. Articles by Ono, M.

N-myc Downstream Regulated Gene 1/Cap43 Suppresses Tumor Growth and Angiogenesis of Pancreatic Cancer through Attenuation of Inhibitor of B Kinase β Expression

¹ Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences and ² Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan; ³ Research Center for Innovative Cancer Therapy, Kurume University; ⁴ Department of Pathology, Kurume University Hospital; ⁵ Department of Surgery, Kurume University School of Medicine, Kurume, Japan; ⁶ Department of Molecular Biology, University of Occupational and Environmental Health, Kitakyushu, Japan; and ⁷ Department of Genome Biology, Kinki University School of Medicine, Osaka, Japan

Requests for reprints: Mayumi Ono, Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Phone: 81-92-642-6296; Fax: 81-92-642-6296; E-mail: mono{at}phar.kyushu-u.ac.jp.

Key Words: angiogenesis • NDRG1 • NF-B

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-B (NF-B) signaling attenuation through marked decreases in inhibitor of B kinase (IKK) β expression and IB phosphorylation. Decreased IKKβ expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-B motif. The introduction of an exogenous IKKβ gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity /CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IB 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-B signaling. [Cancer Res 2009;69(12):4983–91]