title: The H6D variant of NAG-1/GDF15 inhibits prostate xenograft growth in vivo.
abstract: BACKGROUND
  Non-steroidal anti-inflammatory drug-activated gene (NAG-1), a divergent member of the transforming growth factor-beta superfamily, has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis. Recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D) of the NAG-1 protein is associated with lower human prostate cancer incidence. The objective of the current study is to investigate the activity of NAG-1 H6D variant in prostate cancer tumorigenesis in vivo.
  
  
  METHODS
  Human prostate cancer DU145 cells expressing the H6D NAG-1 or wild-type (WT) NAG-1 were injected subcutaneously into nude mice and tumor growth was monitored. Serum and tumor samples were collected for subsequent analysis.
  
  
  RESULTS
  The H6D variant was more potent than the WT NAG-1 and inhibited tumor growth significantly compared to control mice. Mice with tumors expressing the WT NAG-1 have greater reduced both body weight and abdominal fat than mice with H6D variant tumors suggesting different activities of the WT NAG-1 and the H6D NAG-1. A significant reduction in adiponectin, leptin, and IGF-1 serum levels was observed in the tumor-bearing mice with a more profound reduction observed with expression of H6D variant. Cyclin D1 expression was suppressed in the tumors with a dramatic reduction observed in the tumor expressing the H6D variant.
  
  
  CONCLUSIONS
  Our data suggest that the H6D variant of NAG-1 inhibits prostate tumorigenesis by suppressing IGF-1 and cyclin D1 expression but likely additional mechanisms are operative.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr. Research Triangle Park, North Carolina 27709, USA.
authors.forename: Xingya
authors.initials: X
authors.lastname: Wang
authors.forename: Kali
authors.initials: K
authors.lastname: Chrysovergis
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Bienstock
authors.forename: Minsub
authors.initials: M
authors.lastname: Shim
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eling
mesh_terms: D052242:Adiponectin / Q000097:blood; D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D052242:Adiponectin; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D020738:Leptin; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I