Parp‐1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane

Abstract

he polyADP-ribosylation reaction is catalyzed by poly(ADP-ribose) polymerase (Parp) family proteins using NAD as a substrate. Parp-1 is a 113-kDa nuclear enzyme which polyADP-ribosylates various nuclear proteins, including Parp-1 itself and histones, after activation by binding to DNA single and double strand breaks. Parp-1 −/− cells show delayed DNA rejoining after treatment with alkylating agents, and a role of Parp-1 in base excision repair and double strand break (DSB) repair has been suggested. 1) Parp-1 −/− cells also display enhanced genomic instability, including chromosome aberration and increased levels of micronuclei formation both in the absence of DNA damage and after DNA damage introduction. 2, 3)In addition, Parp-1 also has a leading role in cell death after DNA damage and Parp-1 overactivation. NAD depletion after DNA damage was abrogated in Parp-1 −/− cells and as a consequence, Parp-1 −/− cells became resistant to cell death induced by severe DNA damage. [4][5][6][7][8] This evidence suggests that loss of Parp-1 function could have a substantial contribution to tumorigenesis, through the introduction of genetic alterations.In fact, we previously demonstrated that Parp-1 −/− mice, harboring exon 1 disruption in Parp-1, showed increased incidences of liver and lung tumors after N-nitrosobis(2-hydroxypropyl)amine administration. Tong et al. 13) It is also known that pharmacological intakes of niacin augment NAD level and increase the latency of the ethylnitrosourea-induced liver carcinogenesis.14) Since Parp-1 is also involved in the transcriptional regulation of various genes, [15][16][17] the impact of Parp-1 deficiency may differ among various types of tumors and among various organs. Therefore, the effect of Parp-1 deficiency on tumorigenesis needs to be investigated in various models of tumorigenesis.In the present study, Parp-1 −/− mice, harboring exon 1 disruption of Parp-1, were treated with azoxymethane (AOM), a potent colon carcinogen. We observed that the Parp-1 −/− mice showed an enhanced incidence of tumor development in the colon and also in the liver. Colon tumors induced by AOM in rodents are frequently associated with alteration of the Wnt-β-catenin signaling cascade, and β-catenin accumulation is observed.18) Therefore, to examine whether the development of tumors in Parp-1 +/+ and Parp-1 −/− mice involves alteration of Wnt-β-catenin signaling, immunostaining of β-catenin was carried out. Materials and Methods Parp-1−/− mice generated by disrupting the Parp-1 exon 1 through the insertion of a neomycin resistance gene cassette 5) were used in this study. Mice were housed in plastic cages in an air-conditioned room with a 12 h light-dark cycle. Water and basal diet (CE-2, CLEA JAPAN, Tokyo) were available ad libitum. Parp-1 +/+ and Parp-1 −/− female mice (7-8 weeks old) of a mixed genetic background of ICR and 129Sv were produced by line-breeding. The mean body weights of Parp-1 + / + and Parp-1 −/− mice at the start of the experiment were 21.7±1.7 g and 21.4±2.9 g, respectively. P...

Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma

“…Consistent with this hypothesis, PARP1-deficient mice show an elevated incidence of chemically induced colon tumors compared with PARP1-proficient mice (31).…”

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

“…Although the use of PARP inhibitors to potentiate chemo and radiotherapy has been a longstanding approach from different laboratories in the last decades, all the results reported so far in PARP-1 knockout mice show a tumor type-dependent effect of single parp-1 elimination with respect to carcinogenesis. In this respect, recent reports by Tsutsumi et al (2001) and Nozaki et al (2003) indicates that parp-1 knockout mice are more sensitive to chemically induced tumorigenesis in liver and colon, respectively. We think that this controversy is only apparent because the balance between environmental factors (the influence of chronic inflammation and trans-activation of stress-related genes by the tumor and surrounding tissues) and intrinsic components involved in genetic instability of the tumor, is dependent on the type of tumor in study.…”

Poly(ADP-ribosyl)ation by PARP-1: `PAR-laying' NAD+ into a nuclear signal

“…Although Parp-1 −/− mice do not exhibit a propensity for the development of early onset tumors, they do show increased tumor formation in several chemically induced and transgenic cancer models (Table 1; Masutani et al 2005). For example, Parp-1 −/− mice treated with certain alkylating agents [e.g., N-nitrosobis(2-hydroxypropyl)amine and azoxymethane] have a higher incidence of colon and liver cancers than Parp-1 +/+ mice (Tsutsumi et al 2001;Nozaki et al 2003). The incidence of tumors in response to some other DNA-damaging agents, however, is not different between Parp-1 −/− and Parp-1 +/+ mice , suggesting that the nature of the DNA damage dictates the specific contribution of PARP-1 to cancer prevention.…”