<i>Fusobacterium nucleatum</i> promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation

Abstract

The anaerobic bacterium <i>Fusobacterium nucleatum</i> is significantly associated with human colorectal cancer (CRC) and is considered a significant contributor to the disease. The mechanisms underlying the promotion of intestinal tumor formation by <i>F. nucleatum</i> have only been partially uncovered. Here, we showed that <i>F. nucleatum</i> releases a metabolite into the microenvironment that strongly activates NF-κB in intestinal epithelial cells via the ALPK1/TIFA/TRAF6 pathway. Furthermore, we showed that the released molecule had the biological characteristics of ADP-heptose. We observed that <i>F. nucleatum</i> induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC, <i>BIRC3</i> and <i>TNFAIP3</i>. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity <i>in vitro</i>. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in <i>Fusobacterium</i> induced-CRC pathogenesis, and identify the role of ADP-H in this process.