Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer

J. Michels, J. Adam, A. Goubar, F. Obrist, D. Damotte, A. Robin, M. Alifano, I. Vitale, K. A. Olaussen, P. Girard, I. Cremer, M. Castedo, J. C. Soria, G. Kroemer

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Patients and 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)2470-2477
Number of pages8
JournalAnnals of Oncology
Volume26
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

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Pyridoxal Kinase
Poly Adenosine Diphosphate Ribose
Non-Small Cell Lung Carcinoma
Vitamin B Complex
Cisplatin
Proteins
Down-Regulation
Multivariate Analysis
Biomarkers
Immunohistochemistry
Poly (ADP-Ribose) Polymerase-1
Apoptosis

Keywords

  • Niacin
  • Nicotinamide adenine dinucleotide
  • poly ADP-ribosylation
  • Prognostic biomarker
  • Vitamin B6

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Michels, J., Adam, J., Goubar, A., Obrist, F., Damotte, D., Robin, A., ... Kroemer, G. (2015). Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer. Annals of Oncology, 26(12), 2470-2477. https://doi.org/10.1093/annonc/mdv393

Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer. / Michels, J.; Adam, J.; Goubar, A.; Obrist, F.; Damotte, D.; Robin, A.; Alifano, M.; Vitale, I.; Olaussen, K. A.; Girard, P.; Cremer, I.; Castedo, M.; Soria, J. C.; Kroemer, G.

In: Annals of Oncology, Vol. 26, No. 12, 01.12.2015, p. 2470-2477.

Research output: Contribution to journalArticle

Michels, J, Adam, J, Goubar, A, Obrist, F, Damotte, D, Robin, A, Alifano, M, Vitale, I, Olaussen, KA, Girard, P, Cremer, I, Castedo, M, Soria, JC & Kroemer, G 2015, 'Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer', Annals of Oncology, vol. 26, no. 12, pp. 2470-2477. https://doi.org/10.1093/annonc/mdv393
Michels, J. ; Adam, J. ; Goubar, A. ; Obrist, F. ; Damotte, D. ; Robin, A. ; Alifano, M. ; Vitale, I. ; Olaussen, K. A. ; Girard, P. ; Cremer, I. ; Castedo, M. ; Soria, J. C. ; Kroemer, G. / Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer. In: Annals of Oncology. 2015 ; Vol. 26, No. 12. pp. 2470-2477.
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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. Patients and 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. Conclusion: 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.",
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AU - Michels, J.

AU - Adam, J.

AU - Goubar, A.

AU - Obrist, F.

AU - Damotte, D.

AU - Robin, A.

AU - Alifano, M.

AU - Vitale, I.

AU - Olaussen, K. A.

AU - Girard, P.

AU - Cremer, I.

AU - Castedo, M.

AU - Soria, J. C.

AU - Kroemer, G.

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N2 - 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. Patients and 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. Conclusion: 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.

AB - 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. Patients and 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. Conclusion: 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.

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