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Inhibition of Poly(ADP-Ribose) Polymerase Modulates Tumor-Related Gene Expression, Including Hypoxia-Inducible Factor-1 Activation, during Skin Carcinogenesis

¹ Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Cientificas; ² Department of Cell Biology, Faculty of Sciences, ³ Department of Pathology, and ⁴ IBIMER, University of Granada, Granada, Spain; and ⁵ Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Requests for reprints: F. Javier Oliver, Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Cientificas, Avda del Conocimiento s/n, 18100 Armilla, Granada, Spain. Phone: 34-958-181655; Fax: 34-958-181632; E-mail: joliver{at}ipb.csic.es.

Poly(ADP-ribose) polymerase (PARP)-1, an enzyme that catalyzes the attachment of ADP ribose to target proteins, acts as a component of enhancer/promoter regulatory complexes. In the present study, we show that pharmacologic inhibition of PARP-1 with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) results in a strong delay in tumor formation and in a dramatic reduction in tumor size and multiplicity during 7,12-dimethylbenz(a)anthracene plus 12-O-tetradecanoylphorbol-13-acetate–induced skin carcinogenesis. This observation was parallel with a reduction in the skin inflammatory infiltrate in DPQ-treated mice and tumor vasculogenesis. Inhibition of PARP also affected activator protein-1 (AP-1) activation but not nuclear factor-B (NF-B). Using cDNA expression array analysis, a substantial difference in key tumor-related gene expression was found between chemically induced mice treated or not with PARP inhibitor and also between wild-type and parp-1 knockout mice. Most important differences were found in gene expression for Nfkbiz, S100a9, Hif-1, and other genes involved in carcinogenesis and inflammation. These results were corroborated by real-time PCR. Moreover, the transcriptional activity of hypoxia-inducible factor-1 (HIF-1) was compromised by PARP inhibition or in PARP-1–deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1. Tumor vasculature was also strongly inhibited in PARP-1–deficient mice and by DPQ. In summary, this study shows that inhibition of PARP on itself is able to control tumor growth, and PARP inhibition or genetic deletion of PARP-1 prevents from tumor promotion through their ability to cooperate with the activation AP-1, NF-B, and HIF-1. (Cancer Res 2006; 66(11): 5744-56)

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