Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors
Year: 2024
Type: article
Abstract: Mechanisms by which Porphyromonas gingivalis ( P. gingivalis ) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that P. gingivalis infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, P. gingivalis targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type P. gingivalis prevented ceramide-dependent mitophagy. Moreover, a FimA-deletion mutant P. gingivalis variant had no inhibitory effects on ceramide-dependent mitophagy. Further, 16S rRNA sequencing of oral tumors indicated that P. gingivalis infection altered the microbiome of the tumor macroenvironment in response to ceramide analog treatment in mice. Thus, these data provide a mechanism describing the pro-survival roles of P. gingivalis in oral tumors.
Source: iScience
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,150
Funders: Medical University of South Carolina, National Institutes of Health, Hollings Cancer Center, Medical University of South Carolina, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research
Awards: G1410469566, EXTRAMURAL RESEARCH FACILITIEIS CONSTRUCTION, G1845137525, Turning on Persistence: Novel Molecular Determinants that Underpin P. gingivalis Intracellular Survival In Epithelial Cells, G3410771321, Confocal/Multiphoton Microscope Upgrade, Development of Novel Cancer Therapeutics by Targeting Sphingolipid Signaling, Sphingolipid Metabolism and Signaling in the Regulation of Senescence and Aging, COBRE in Lipidomics and Pathobiology, G9000183288, G9000204985, T-COHR: Training in Craniofacial and Oral Health Research, Ceramide Signaling in the Regulation of Head & Neck Cancer Cell Death and Therapy, Medical University of South Carolina - Cancer Center Support Grant, MUSC Digestive Disease Research Core Center, Ceramide metabolism and the regulation of PD-L1 signaling to control metastasis and resistance to immunotherapy in TNBC
OpenAlex ID: W4396534093