Journal Article

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

Kaina, Bernd, Stroh, Svenja, Fahrer, Jörg, Dantzer, Françoise, Diehl, Erika, Dörsam, Bastian, Nagel, Georg, Waisman, Ari, Seiwert, Nina, Kraus, Alexander, Roukos, Vassilis, Foersch, Sebastian, Moehler, Markus, Begaliew, Diana, Stier, Anna, Reißig, Sonja, Minneker, Vera, Mangerich, Aswin, McKeague, Maureen

2018

Overview

Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1−/−) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1−/− mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1−/− animals were then crossed with O⁶-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1−/−/MGMT−/− double knockout (DKO) mice developed more, but much smaller tumors than MGMT−/− animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O⁶-methylguanine levels. Studies with PARP-1−/− cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O⁶-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression.

• Publisher: National Academy of Sciences
• Subject: Adducts / Adenosine diphosphate / Alkylation / Animals / Autophagy / Azoxymethane / Biological Sciences / Carcinogenesis / Carcinogens / Cell death / Cell Line, Tumor / Colorectal cancer / Colorectal Neoplasms - enzymology / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Colorectal Neoplasms - prevention & control / Cyclin D1 / Cytokines / Deoxyribonucleic acid / Dextran / DNA / DNA damage / DNA methyltransferase / DNA microarrays / DNA repair / Genotypes / Guanine - analogs & derivatives / Guanine - metabolism / Humans / Immune system / Inflammation / Inflammatory bowel diseases / Intestine / Life Sciences / Medical Sciences / Methylguanine / Mice / Mice, Knockout / O6-methylguanine-DNA methyltransferase / Phagocytosis / PNAS Plus / Poly (ADP-Ribose) Polymerase-1 - genetics / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) / Poly(ADP-ribose) polymerase / Proteins / Repair / Ribose / Sodium / Sodium sulfate / Tissue analysis / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors