Obese serum factors aggravate DNA damage, alter DNA damage response, and promote proliferation in colon cancer cells

Clinical data indicate a positive association between obesity and DNA damage, which has been implicated in several pathological conditions. Obesity also increases the risk of the development and progression of cancers, including colon cancer. However, the underlying mechanisms linking obesity-induced alterations in the DNA damage response (DDR) to colon cancer remain largely unexplored. The present study aims to investigate the functional status of the cellular DNA damage response in an obese environment and its association with colon cancer. To address this, cells were cultured in media supplemented with serum collected from mice fed a normal-fat diet (ND) and a high-fat diet (HFD). Subsequently, the DNA damage response and associated phenotypic parameters were evaluated. Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage along with reduced levels of DNA repair molecules, together with activation of the DDR, as indicated by elevated levels of pH2AX, P-p53Ser15, and pchk2 proteins. Moreover, cell growth assays demonstrated rapid proliferation of cells cultured in HFD serum. Furthermore, HFD-fed C57BL6/J mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher incidence of colon polyps compared to ND-fed mice. Interestingly, in ATM knockout mice (ATM, a key DDR-related molecule), a higher occurrence of polyps was detected compared to ATM wild-type mice, suggesting a potential role of ATM in polyp formation. Thus, by perturbing DDR and DNA repair pathways and promoting cell survival, obesity creates a favorable environment for cell proliferation. Collectively, this pre-clinical study enhances our understanding of obesity-altered DDR and its association with cancer cell proliferation.