The role of N-myc downstream regulated gene-1 (NDRG1) in cancer has recently gained interest, as potential regulator of cell death and tumor suppressor. Although its normal function in the pancreas is largely unknown, loss of NDRG1 expression is associated with a more aggressive tumor phenotype and poor outcome in pancreatic cancer patients.
NDRG1 expression was determined in human pancreatic cancer samples and across a panel of 6 pancreatic cancer cell lines. HPAF-II cells were stably transfected with full-length NDRG1 (HPNDRG1) or the empty vector (HPNEG). BxPC-3 cells were silenced for NDRG1. These cells were analyzed for cell growth, cell cycle, apoptosis, and pro-apoptotic gene expression. They were transduced with lentiviral vector expressing luciferase to establish an orthotopic xenograft model. In vivo tumor growth was assessed by bioluminescence imaging.
Growth of HPNDRG1 was impaired in anchorage-dependent and abolished in anchorage-independent assays respectively. These results were confirmed in BxPC-3 silenced for NDRG1. Growth inhibition was induced by enhanced apoptosis. Seven pro-apoptotic genes were up-regulated in HPNDRG1 cells. In vivo, HPNDRG1 tumors showed no growth over 6 weeks, while HPNEG tumors grew prominently, correlating with a 325-fold increase in light emission.
In this model we found that expression of NDRG1 correlates with decreased growth in human pancreatic cancer cells in vitro and in vivo. The observation that NDRG1 completely inhibited growth in anchorage-independent assays and in vivo supports a biological function as a tumor suppressor in pancreatic cancer.
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- Cancer statistics, 2009.CA Cancer J Clin. 2009; 59: 225-249
- Improved survival following pancreaticoduodenectomy to treat adenocarcinoma of the pancreas: the influence of operative blood loss.Arch Surg. 2008; 143: 1166-1171
- National failure to operate on early stage pancreatic cancer.Ann Surg. 2007; 246: 173-180
- Current trends in the diagnosis and treatment of carcinoma of the pancreas.Am J Surg. 1983; 145: 813-818
- An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma.Cancer. 1999; 85: 1261-1268
- Current chemotherapeutic possibilities in pancreaticobiliary cancer.Ann Oncol. 1999; 10: 157-161
- Apoptotic pathways in pancreatic ductal adenocarcinoma.Mol Cancer. 2008; 7: 64
- Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer.Cancer Res. 2000; 60: 749-755
- Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis.Cancer Res. 2006; 66: 6233-6242
- Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage.Cancer Res. 1998; 58: 4439-4444
- NDRG1 is necessary for p53-dependent apoptosis.J Biol Chem. 2004; 279: 48930-48940
- Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells.Biochim Biophys Acta. 1999; 1450: 364-373
- Identification of a stress-induced protein during human trophoblast differentiation by differential display analysis.Biol Reprod. 1999; 61: 681-686
- Antiproliferative effects of AVN944, a novel inosine 5-monophosphate dehydrogenase inhibitor, in prostate cancer cells.Int J Cancer. 2008; 123: 2294-2302
- The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells.FEBS Lett. 1999; 455: 23-26
- Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects.Int J Oncol. 2004; 25: 631-639
- NDRG1 contributes to retinoic acid-induced differentiation of leukemic cells.Leuk Res. 2009; 33: 1108-1113
- Egr-1 Mediates hypoxia-inducible transcription of the NDRG1 Gene through an overlapping Egr-1/Sp1 binding site in the promoter.Cancer Res. 2007; 67: 9125-9133
- PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.Cancer Res. 2004; 64: 7655-7660
- p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion.Am J Physiol Cell Physiol. 2007; 293: C379-C389
- Expression of NDRG1, a differentiation-related gene, in human tissues.Histochem Cell Biol. 2002; 118: 399-408
- Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer.Br J Cancer. 2006; 95: 307-313
- A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms.Lab Invest. 1997; 77: 85-92
- The Drg-1 gene suppresses tumor metastasis in prostate cancer.Cancer Res. 2003; 63: 1731-1736
- The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc.Mol Cell Biochem. 2003; 250: 91-105
- Seven genes that are differentially transcribed in colorectal tumor cell lines.Cancer Lett. 2000; 160: 37-43
- N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression.Cancer Res. 2009; 69: 4983-4991
- Epigenetic regulation affects N-myc downstream-regulated gene 1 expression indirectly in pancreatic cancer cells.Pancreas. 2010; 39: 675-679
- The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling.Cancer Res. 2005; 65: 11536-11544
- Mononuclear cell-derived interleukin-1 beta confers chemoresistance in pancreatic cancer cells by upregulation of cyclooxygenase-2.Surgery. 2008; 144: 57-65
- An orthotopic nude mouse model for evaluating pathophysiology and therapy of pancreatic cancer.Pancreas. 2003; 26: e89-e98
- Bioluminescence imaging of angiogenesis in a murine orthotopic pancreatic cancer model.Mol Imaging Biol. 2010; 12: 570-575
- Caveolin-1 inhibits breast cancer growth and metastasis.Oncogene. 2004; 23: 7893-7897
- Tumor-stroma interactions in pancreatic ductal adenocarcinoma.Mol Cancer Ther. 2007; 6: 1186-1197
- Pancreatic fibrosis associated with age and ductal papillary hyperplasia.Virchows Arch. 2005; 447: 800-805
- Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines.Cancer Res. 2004; 64: 3052-3059
- Modeling dynamic reciprocity: engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation.Semin Cancer Biol. 2005; 15: 342-352
- Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways.Gastroenterology. 2003; 125: 1188-1202
- N-Myc down-regulated gene 1 mediates proliferation, invasion, and apoptosis of hepatocellular carcinoma cells.Cancer Lett. 2008; 262: 133-142
- Caspases in apoptosis and beyond.Oncogene. 2008; 27: 6194-6206
- Interferon gamma inhibits growth of human pancreatic carcinoma cells via caspase-1 dependent induction of apoptosis.Gut. 2001; 49: 251-262
- The TRAIL apoptotic pathway in cancer onset, progression and therapy.Nat Rev Cancer. 2008; 8: 782-798
- Anoikis: a necessary death program for anchorage-dependent cells.Biochem Pharmacol. 2008; 76: 1352-1364
- Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch.Cell Cycle. 2006; 5: 1779-1787
Published online: January 18, 2011
Accepted: November 9, 2010
Supported by the National Institutes of Health (P01AT003960, R01CA104027, R01CA122042, R21CA124609) (O.J.H. and G.E.), the Swiss National Science Foundation (PBZHB-117008) (E.A.), Department of Clinical Research, University of Bern, Bern, Switzerland (E.A.), and the Hirshberg Foundation for Pancreatic Cancer Research (H.A.R.).
© 2011 Mosby, Inc. Published by Elsevier Inc. All rights reserved.