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

ABSTRACT

The anaerobic bacterium Fusobacterium nucleatum 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 F. nucleatum have only been partially uncovered. Here, we showed that F. nucleatum 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 F. nucleatum induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC, BIRC3 and TNFAIP3. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity in vitro. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in Fusobacterium induced-CRC pathogenesis, and identify the role of ADP-H in this process.

KEYWORDS:

• Fusobacterium
• ALPK1
• colorectal cancer
• NF–κB

Acknowledgments

We are grateful to Dr. Marion Espeli (INSERM U1160) for helpful discussions, critical comments, and corrections on the manuscript. The authors are grateful to Dr. Anne Letessier (Institut Cochin), Dr. Benoit Miotto (Institut Cochin) for their helpful discussion. The authors are grateful to Amandine Lashermes for technical input, Agnès David (INRAE, UMR 1280 PHAN, Nantes, France) and Camille Mayeur (INRAE Micalis) for SCFA analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors contributions

Conceived and designed the experiments: CMG, CA, NL; intellectual contribution: JD, HMB; data acquisition: CMG, LS, DGW, LM, FBC, CLG, VB, AJ, CA, NL; data analysis, statistical analysis, and interpretation: CMG, DGW, CA, and NL; wrote the paper: CMG, NL; edited and revised the manuscript: JD, HMB, CA, DGW, and LM.

Data availability statement

All data are contained in the article and the supporting information.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2295384

Additional information

Funding

The work was supported by the Agence Nationale de la Recherche [ANR-17-CE15-0006]; Agence Nationale de la Recherche [ANR-22-CE14-0046]; Association Francois Aupetit [Bourse de Recherche]; Institut National Du Cancer [Plbio-2021-101]; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement [“Projet jeune chercheur du département AlimH”]; Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche [PhD fellowship]; Université Paris-Saclay [PhD fellowship].