Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin.

Abstract

Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.

• Authors: Pachiyappan Kamarajan, Islam Ateia, Jae M Shin, J Christopher Fenno, Charles Le, Ling Zhan, Ana Chang, Richard Darveau, Yvonne L Kapila
• Journal: PLoS pathogens (PLoS Pathog) Vol. 16 Issue 10 Pg. e1008881 (10 2020) ISSN: 1553-7374 [Electronic] United States
• PMID: 33002094 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Integrins
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• TLR2 protein, human
• Toll-Like Receptor 2
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Animals
• Apoptosis
• Bacteroidaceae Infections (drug therapy, metabolism, microbiology, pathology)
• Carcinoma, Squamous Cell (drug therapy, metabolism, microbiology, pathology)
• Cell Movement
• Cell Proliferation
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Humans
• Integrins (genetics, metabolism)
• Mice
• Mice, Nude
• Mouth Neoplasms (drug therapy, metabolism, microbiology, pathology)
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Periodontitis (drug therapy, metabolism, microbiology, pathology)
• Porphyromonas gingivalis (drug effects, pathogenicity)
• Probiotics (pharmacology)
• Toll-Like Receptor 2 (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays