Tumour necrosis factor-α (TNF-α) enhances dietary carcinogen-induced DNA damage in colorectal cancer epithelial cells through activation of JNK signaling pathway

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazol [4,5-b] pyridine (PhIP) present in cooked meat are pro-carcinogens and considered to be potential risk factors for CRC. Their carcinogenic and mutagenic effects require metabolic activation primarily by cytochrome P450 1 family enzymes (CYPs); the expression of these enzymes can be modulated by aryl hydrocarbon receptor (AhR) activation and the tumour microenvironment, involving mediators of inflammation. In this study, we hypothesized that tumour necrosis factor-alpha (TNF-alpha), a key mediator of inflammation, modulates BaP- and PhIP-induced DNA damage in colon cancer epithelial cells. Importantly, we observed that TNF-alpha alone (0.1-100 pg/ml) induced DNA damage (micronuclei formation) in HCT-116 cells and co-treatment of TNF-alpha with BaP or PhIP showed higher levels of DNA damage compared to the individual single treatments. TNF-alpha alone or in combination with BaP or PhIP did not affect the expression levels of CYP1A1 and CYP1B1 (target genes of AhR signaling pathways). The DNA damage induced by TNF-alpha was elevated in p53 null HTC-116 cells compared to wild type cells, suggesting that TNF-alpha-induced DNA damage is suppressed by functional p53. In contrast, p53 status failed to affect BaP and PhIP induced micronucleus frequency. Furthermore, JNK and NF-kappa B signaling pathway were activated by TNF-alpha treatment but only inhibition of JNK significantly reduced TNF-alpha-induced DNA damage. Collectively, these findings suggest that TNF-alpha induced DNA damage involves JNK signaling pathway rather than AhR and NF-kappa B pathways in colon cancer epithelial cells.

Automated summary

The study revealed that the inflammation mediator TNF-alpha can enhance DNA damage induced by BaP and PhIP in colon cancer epithelial cells, without affecting the gene expression levels of the AhR signaling pathways. Additionally, functional p53 suppresses TNF-alpha-induced DNA damage, while the JNK signaling pathway plays a crucial role in this process.