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

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

^* To whom correspondence should be addressed. E-mail: mono{at}phar.kyushu-u.ac.jp.

	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-B (NF-B) signaling attenuation through marked decreases in inhibitor of B kinase (IKK) expression and IB phosphorylation. Decreased IKK 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 IKK 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]

Key Words: angiogenesis, NDRG1, NF-B