Crosstalk between PARP-1 and NF-κB modulates the promotion of skin neoplasia

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-jB, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1 À/À mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumorbearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1 À/À mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-jB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-jB activation and induction jB-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-jB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.

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

“…A short initiation/promotion protocol was used to assess for changes in NF-nB and AP-1 activation, HIF-1a, and genomic expression profiles of skin epithelial cells in the initial steps of carcinogenesis with or without DPQ inhibitor as that by Martin-Oliva et al (6). This treatment consisted in a single dose of 7,12-dimethylbenz(a)anthracene (DMBA; 25 Ag) and four doses of 12 Ag TPA with or without 30 Ag DPQ given 7 days (6) before evaluation of NF-nB and AP-1 activation, HIF-1a, and differential genes expression.…”

“…NF-KB, AP-1, and HIF-1A-binding activity. Gel shift assays were used to detect NF-nB, AP-1, and HIF-1a-binding activity as that by Martin-Oliva et al (6) and Lok et al (7).…”

“…Tumor induction in mice on the C57BL/6 background was done as described previously (6), except that one group was treated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ; Alexis Biochemicals, San Diego, CA), inhibitor of PARP, and applied simultaneously with 12-Otetradecanoylphorbol-13-acetate (TPA). Control animals were also treated in parallel with acetone alone.…”

“…(5). In a previous report, we have shown that parp-1 knockout (KO) mice are protected against chemically induced skin carcinogenesis (6). In the present study, we show that the inhibition of PARP activity prevents from tumor growth during skin carcinogenesis due to its ability to modulate the activity of key transcription factors involved in tumor promotion (such as AP-1 and HIF-1) and also to interfere with the expression of genes involved in both tumor promotion/ progression and inflammation.…”

A General Sight about Linking PARP-1 and NFKB1 Variations to the Inflammatory Events

“…In DNA-damaged cell, the damage is recognized by PARP-1 in a short time which in turn, affects many proteins to form a structure, and acts as a transcriptional coactivator of NFKB in cell nucleus [6,[21][22][23]. PARP-1 uses NAD+ to form (ADP-ribose) polymers on target proteins [24].…”