THE DUAL ACTIONS OF DNA REPAIR ENZYME, PARP‐1, IN COLON INFLAMMATION AND CARCINOGENESIS
Authors: Tarhuni Abdelmetalab Fergani , Errami Youssef , El‐Bahrawy Ali Hassan , Al‐Khami Amir , Gohnim Mohamed , Naura Amarjit , Dean Matthew , Pyakurel Kusma , Wang Jeffrey , Brim Hassan , Ashktorab Hassan , Rodriguez Paulo C , Ochoa Augusto , Boulares Hamid 
Published: November 2023

Colon cancer is one of the leading causes of death in the United States. Genomic instability and chronic colonic inflammation are the main causes of colon cancer. Mutation in any of the components of the β‐catenin destruction complex, mainly in adenomatous polyposis coli (APC) protein, leads to over proliferation of colon epithelial cells and may result in tumor formation in the colon or rectum. Additionally, chronic inflammatory diseases such colitis upregulate inflammatory markers that may inhibit DNA repair enzymes, cause aberrant activation of β‐catenin, and induce mutation and activation of transcription factors such as STAT3 and NF‐κB. These events lead to uncontrolled cell proliferation and may cause colon tumor formation. Poly‐(ADP‐ribose)‐polymerase I (PARP‐1) is an enzyme that is critically involved in several cellular processes such as DNA repair, apoptosis, genomic stability, and inflammation. Because PARP‐1 plays a role in colon tissue homeostasis, inhibition of PARP‐1 may promote colon carcinogenesis by inhibiting DNA repair and causing genomic instability. On the other hand, our lab has previously shown that PARP‐1 inhibition results in reduced inflammation in both acute and chronic models of inflammatory diseases, which gives us additional evidence that PARP‐1 contributes to colon carcinogenesis. I thus hypothesize that inhibition of PARP‐1 (A) may promote colon tumorigenesis if genomic stability is the predominant driver in colon carcinogenesis but (B) may reduce colon tumorigenesis if inflammation is the major driver of the disease. To test this hypothesis I have used three animal models: the ApcMin/+ mouse model, which develops spontaneous intestinal tumors; a combined carcinogen based/chronic inflammation induced (AOM+DSS) model; and an MCA‐38 cell based allograft model. When genetic mutation is the primary driver of carcinogenesis (as in the ApcMin/+ mouse model), inhibition of PARP‐1 function through gene deletion resulted in a reduced tumor burden in heterozygous (ApcMin/+/PARP+/−) mice, but an increased tumor burden in homozygous (ApcMin/+/PARP−/−) mice. In support of this, inhibition of PARP‐1 by olaparib (a PARP‐1 inhibitor used in clinical trials) reduced intestinal tumor burden in ApcMin/+/PARP+/+ mice. Both genetic and pharmacological inhibition of PARP‐1 suppressed inflammation as evaluated by inflammatory markers (iNOS, VCAM‐1, and TNF‐a), and, in our chronic inflammation driven model (AOM/DSS), PARP‐1 knockout showed significant reduction in colon tumorigenesis compared to wild type mice. PARP‐1 nullizigosity promoted a tumor‐suppressive rather than a tumor‐promoting host response as shown by our MCA‐38‐ allograft data. Taken together, these data reveal that, while PARP‐1 is an attractive candidate for therapeutics due to its clear role in the two primary processes leading to colon cancer development, more work has to be done to determine which specific conditions are necessary for PARP‐1 inhibition to reduce – rather than promote ‐ tumorigenesis.

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ACS, NIH, Stanley S. Scott Cancer Center, and CBIE