Abstract

It is well known that inflammation is a key component in the initiation and progression of epithelial cancer [1]. In a recent studies [2] we have established that the absence of PARP-1 is able to slow down tumour formation and to increase the lifespan of p53 deficient mice. We and others have shown that PARP-1 is a transcriptional co-activator of NF-kB and PARP-1 knockout as a result of a diminished release of pro-inflammatory mediators, including NO [3,4]. In the present report we have studied the susceptibility to skin carcinogenesis in mice deficient for poly(ADP-ribose) polymerase-1. In PARP-1–/– mice development of skin tumours induced by initiation with DMBA and promotion with TPA is strongly delayed, and the final number of tumour-bearing mice and total tumour number were significantly decreased in genetically deficient mice for PARP-1. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. Nonetheless, epidermis of PARP-1–/– mice did not show increased proliferation rates. Derregulated NF-kB has been proven to be a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators, such as TNF-a. In the absence of PARP-1 NF-kB activation and induction of TNF-a did not take place during the initiation of tumour development in cell extracts from the epidermis of the carcinogen-treated area. In view of the important roles of NF-kB in tumour promotion/progression, these results suggest that inhibition of tumour development by the abolition of PARP-1 may be mediated by impairing signal transduction pathways leading to activation of NF-kB. References: 1.Correa P: Cancer Res, 1992; 52; 6735-6740 2.Conde C, Mark M, Oliver FJ et al: EMBO Journal, 2001; 20: 3535-3543 3.Oliver FJ, Ménissier de Murcia J, Nacci C et al: EMBO Journal, 1999; 18: 4446-4454 4.Hassa PO, Covic M, Hasan S et al: J Biol Chem, 2001 Dec 7; 276(49): 45588-97

Keywords: PARP-1 knockout mice, skin carcinogenesis, NF-kB, TNF-a