title: Cancer stem cell overexpression of nicotinamide N-methyltransferase enhances cellular radiation resistance.
abstract: BACKGROUND
  Cancer stem cells are thought to be a radioresistant population and may be the seeds for recurrence after radiotherapy. Using tumorigenic clones of retroviral immortalized human mesenchymal stem cell with small differences in their phenotype, we investigated possible genetic expression that could explain cancer stem cell radiation resistance.
  
  
  METHODS
  Tumorigenic mesenchymal cancer stem cell clones BB3 and CE8 were irradiated at varying doses and assayed for clonogenic surviving fraction. Altered gene expression before and after 2 Gy was assessed by Affymetric exon chip analysis and further validated with q-RT-PCR using TaqMan probes.
  
  
  RESULTS
  The CE8 clone was more radiation resistant than the BB3 clone. From a pool of 15 validated genes with altered expression in the CE8 clone, we found the enzyme nicotinamide N-methyltransferase (NNMT) more than 5-fold upregulated. In-depth pathway analysis found the genes involved in cancer, proliferation, DNA repair and cell death.
  
  
  CONCLUSIONS
  The higher radiation resistance in clone CE8 is likely due to NNMT overexpression. The higher levels of NNMT could affect the cellular damage resistance through depletion of the accessible amounts of nicotinamide, which is a known inhibitor of cellular DNA repair mechanisms.
authors: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. filippo@oncology.dk
authors: Filippo P
authors: FP
authors: D'Andrea
authors: Akmal
authors: A
authors: Safwat
authors: Moustapha
authors: M
authors: Kassem
authors: Laurant
authors: L
authors: Gautier
authors: Jens
authors: J
authors: Overgaard
authors: Michael R
authors: MR
authors: Horsman
mesh_terms: D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D002869:Chromosome Aberrations; D016207:Cytokines / Q000378:metabolism; D005091:Exons; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000528:radiation effects*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000528:radiation effects*; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D010641:Phenotype; D011836:Radiation Tolerance / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D050903:Nicotinamide N-Methyltransferase; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human