title: Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer.
abstract: BACKGROUND
  Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC.
  
  
  METHODS
  We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC.
  
  
  RESULTS
  Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification.
  
  
  CONCLUSIONS
  NSCLC patients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Department of Medical Oncology, Gustave Roussy Comprehensive Cancer Center, Villejuif Paris-Sud University, Villejuif.
authors.forename: J
authors.initials: J
authors.lastname: Michels
authors.affiliation: Paris-Sud University, Villejuif Department of Pathology, Gustave Roussy Comprehensive Cancer Center, Villejuif INSERM U981, Villejuif.
authors.forename: J
authors.initials: J
authors.lastname: Adam
authors.affiliation: INSERM U981, Villejuif.
authors.forename: A
authors.initials: A
authors.lastname: Goubar
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Obrist
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Department of Pathology and Thoracic Surgery, Cochin Hospital, AP-HP, Paris Paris Descartes University, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Damotte
authors.affiliation: INSERM U981, Villejuif.
authors.forename: A
authors.initials: A
authors.lastname: Robin
authors.affiliation: Department of Pathology and Thoracic Surgery, Cochin Hospital, AP-HP, Paris Paris Descartes University, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Alifano
authors.affiliation: Regina Elena National Cancer Institute, Rome Department of Biology, University of Rome 'TorVergata', Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Vitale
authors.affiliation: Paris-Sud University, Villejuif INSERM U981, Villejuif.
authors.forename: K A
authors.initials: KA
authors.lastname: Olaussen
authors.affiliation: Thoracic Department, Mutualiste Montsouris Institute, Paris.
authors.forename: P
authors.initials: P
authors.lastname: Girard
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Paris Descartes University, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Cremer
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris.
authors.forename: M
authors.initials: M
authors.lastname: Castedo
authors.affiliation: Paris-Sud University, Villejuif INSERM U981, Villejuif Department of Drug Development, Gustave Roussy Comprehensive Cancer Center, Villejuif.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Paris Descartes University, Paris, France Metabolomics Platform, Gustave Roussy Comprehensive Cancer Center, Villejuif Department of Biology, Georges Pompidou European Hospital, AP-HP, Paris, France kroemer@orange.fr.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: niacin; nicotinamide adenine dinucleotide; poly ADP-ribosylation; prognostic biomarker; vitamin B6