Crosstalk between PARP-1 and NF-kappaB modulates the promotion of skin neoplasia.
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-kappaB, 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(-/-) mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumor-bearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1(-/-) mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-kappaB is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-kappaB activation and induction kappaB-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-kappaB and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.
Martín-Oliva
David
D
University Hospital, San Cecilio, Granada.
O'Valle
Francisco
F
Muñoz-Gámez
Jose A
JA
Valenzuela
M Teresa
MT
Nuñez
M Isabel
MI
Aguilar
Mariano
M
Ruiz de Almodóvar
J M
JM
Garcia del Moral
Raimundo
R
Oliver
F Javier
FJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002273:Carcinogens; D002455:Cell Division; D018450:Disease Progression; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008938:Mitosis; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors
D002273:Carcinogens; D016328:NF-kappa B; D015127:9,10-Dimethyl-1,2-benzanthracene; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D013755:Tetradecanoylphorbol Acetate