Porphyromonas gingivalis-derived lipopolysaccharide confers chemotherapy resistance and migratory ability on oral cancer cells by activating toll-like receptor 4 signaling pathway

TL;DR

This study shows that a bacterial component from Porphyromonas gingivalis makes oral cancer cells more resistant to chemotherapy and more mobile by activating a specific signaling pathway.

Contribution

The study reveals a novel mechanism by which P. gingivalis lipopolysaccharide promotes chemotherapy resistance and migration in oral cancer cells via TLR4/NF-κB signaling.

Findings

P. g-LPS reduces 5-FU-induced cell death in oral cancer cells through TLR4/NF-κB activation.

P. g-LPS enhances cell migration and promotes a more aggressive cancer cell phenotype.

Blocking TLR4 or NF-κB signaling reverses the effects of P. g-LPS on chemotherapy resistance and migration.

Abstract

This study examined the Porphyromonas gingivalis-derived lipopolysaccharide (P. g-LPS)-activated-toll-like receptor 4 (TLR4) pathway and its association with resistance to chemotherapy in oral squamous cell carcinoma (OSCC) cells.

The OSCC cell lines OM-1 and HOC621 were used in this study. Cells were treated with P. g-LPS, TAK-242 as a TLR4 inhibitor, SC75741 as a nuclear factor-kappa B (NF-κB) inhibitor, and AH-6809 as a prostaglandin E2 (PGE2) receptor antagonist. 5-Fluorouracil (5-FU)-induced cytotoxicity was investigated by measuring lactate dehydrogenase that leaked from damaged cells. 5-FU-induced cytotoxicity was attenuated by P. g-LPS in OM-1 cells and HOC621 cells, although this attenuation was relieved by TAK-242, TLR4 siRNA knockdown, or SC75741. P. g-LPS induced phosphorylation and nuclear translocation of NF-kB/p65, and enhanced cyclooxygenase 2 (COX2) expression and PGE2 production in OM-1 cells. 5-FU-induced cytotoxicity was enhanced by AH-6809 in P. g-LPS-treated OM-1 cells. Furthermore, P. g-LPS-promoted cell migration was inhibited by TAK-242 or SC75741 in OM-1 cells. This study also involved an additional experiment focusing on CD44high OSCC cells. 5-FU-induced cytotoxicity was attenuated by P. g-LPS in amoeboid CD44high OM-1 cells when cultured on laminin-332-coated silicone gel. Additionally, P. g-LPS enhanced cofilin-1 dephosphorylation and cell protrusion in amoeboid CD44high OM-1 cells.

P. g-LPS is involved in chemotherapy resistance of OM-1 cells by activating the TLR4/NF-kB pathway, which promotes the migratory ability of these cells, and enhancing PGE2 autocrine signaling. P. g-LPS plays a vital role in OSCC cells’ acquisition of a highly malignant phenotype.

The online version contains supplementary material available at 10.1007/s11033-026-11713-1.

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