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

作者：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^*

来源：Annals of Oncology, 2015, 26(12): 2470-2477.

DOI：10.1093/annonc/mdv393

• poly ADP-ribosylation
• nicotinamide adenine dinucleotide
• niacin
• vitamin B6
• prognostic biomarker

Two vitamin B-related mechanisms affect the prognosis of nonsmall cell lung cancer patients: the vitamin B3 precursor of nicotinamide adenine dinucleotide, consumed by the poly(ADP-ribose) polymerase, which covalently adds poly(ADP-ribose) moieties on intracellular proteins; and the conversion of the vitamer pyridoxine into the active vitamin B6 metabolite, by pyridoxine kinase.
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.

• 出版日期2015-12