PARADOXICAL ROLES OF PARP‐1 IN COLON INFLAMMATION AND TUMORIGENESIS

Abstract

Important causes of colon cancer in humans are chronic colon inflammation and the accumulation of mutations. PARP‐1 is involved in genomic stability and inflammatory processes, which are anti‐ and pro‐cancer phenomenon, respectively. We investigated these opposing roles of PARP‐1 in colon carcinogenesis using different models of the disease. Our results show that partial PARP‐1 inhibition by gene heterozygosity conferred a significant protection against ApcMin‐driven intestinal tumor burden. Surprisingly, complete PARP‐1 gene knockout not only did not protect against ApcMin‐driven intestinal tumorigenesis, it actually increased the tumor burden in mice. Inhibition of PARP by a low dose (5mg/kg) of olaparib (an inhibitor used in clinical trials) reduced moderately (although not statistically significant) the tumor burden; however, a higher dose (25 mg/kg) aggravated the tumor burden in ApcMin mice. These opposing outcomes occurred despite the anti‐inflammatory effects provided by either genetic or pharmacological PARP inhibition (assessed by ICAM, INOS, and TNF levels). Interestingly, in the carcinogen/inflammation model, both pharmacological and genetic inhibition of PARP reduced tumor burden in treated mice. In the xenograft model, PARP‐1 gene knockout reduced the size of MCA‐38‐generated tumors demonstrating, potentially, a role for PARP‐1 in the host response to tumor development. Our results demonstrate a complexity in the role of PARP‐1 in colon tumorigenesis and that its paradoxical role in such process should be carefully considered prior to using its inhibition as a therapeutic strategy against colon cancerFunds: ACS and NIH