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

HighlightsO_LIObese serum aggravates DNA damage and reduces levels of DNA repair molecules in colon cancer cells. C_LIO_LIObese serum activates DDR mechanisms by upregulating P-p53ser15 and pchk2. C_LIO_LIATM-/- mice are prone to AOM/DSS induced colon polyp formation. C_LIO_LIObese serum contributes to the survival phenotype of colon cancer cells. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/642555v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@7be6dforg.highwire.dtl.DTLVardef@72794borg.highwire.dtl.DTLVardef@1795a57org.highwire.dtl.DTLVardef@1a36b9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Clinical data indicate a positive link between obesity and DNA damage, which has also been implicated in various pathological conditions. Obesity increases the risk of occurrence and progression of cancers including colon cancer. The underlying mechanisms of the association between obesity-induced alterations in DNA damage response and colon cancer remain unexplored. The present study attempts to investigate the functional status of 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 and high-fat diet. Subsequently, the DNA damage response and phenotypic parameters were evaluated. Experimental results revealed that cells cultured in HFD serum exhibited increased DNA damage and reduced levels of DNA repair molecules together with activation of DDR by upregulating levels of pH2AX, P-p53ser15, and pchk2 proteins. Moreover, the cell growth assay revealed a rapid proliferation of cells cultured in HFD serum. Furthermore, HFD mice administered with azoxymethane/dextran sodium sulfate (AOM/DSS) exhibited a higher occurrence of colon polyps compared to normal diet-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 possible association of ATM with polyp formation. Thus, by perturbing DDR, repair pathways, and increasing cell survival, obesity creates a favorable environment for the proliferation of cells. Collectively, this study advances understanding of obesity-altered DDR and its association with cancer cell proliferation.