Abstract
Abstract
We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells (CECs) exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency is highly associated with colon malignancy in humans. Upon DNA damage caused by a low dose of irradiation, ICAD-/- cells acquire a tumorigenic phenotype. CECs derived from ICAD-/- mice showed a marked resistance to death induced by the colon carcinogen dimethylhydrazine (DMH) in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of DMH-induced colon tumorigenesis, ICAD-/- mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD-/- mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability, constituting most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Our results present a strong case for involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3096. doi:1538-7445.AM2012-3096