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Role of biased signalling mediated by toll-like receptor 4 in glioblastoma cells

Zeuner, M.-T. (2018) Role of biased signalling mediated by toll-like receptor 4 in glioblastoma cells. PhD thesis, University of Reading

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Abstract/Summary

Glioblastoma cancer stem cells are a subpopulation of cells within aggressive brain tumours. These cells are responsible for relapse after chemotherapy or radiotherapy and for the formation of metastases. Toll-like receptor 4 (TLR4) recognises lipopolysaccharides (LPSs) from Gram-negative bacteria and danger/damage-associated molecular patterns (DAMPs). Signalling via TLR4 can activate the transcription factor Interferon regulatory factor 3 (IRF3) and/or nuclear factor 'kappa-light-chain-enhancer' of activated B cells (NF-κB). The pro-inflammatory transcription factor NF-κB stimulates cell motility and proliferation, whereas IRF3 has anti-inflammatory and anti-proliferative properties. My work focuses on the ligand-dependent biased signalling of TLR4 and its effect on cancer stem cell behaviour. In a glioblastoma cancer stem cell-like cell line (U251), we showed that the dynamics and kinetics of TLR4-induced NF-κB- and IRF3-activation is dependent on the nature of the ligand. Escherichia coli LPS promoted activation of NF-κB, upregulation of pro-inflammatory cytokines and increased proliferation. In contrast, Salmonella minnesota LPS triggered activation and nuclear translocation of IRF3, up-regulation of the anti-inflammatory IFN, while migration was decreased compared to cells exposed to E. coli LPS. We further demonstrated that TLR4-mediated signalling was dependent on TLR4 dimerisation at the plasma membrane and on the localisation of TLR4 in microdomains. The cancer stem cell marker CD133 was increased in U251 cells after exposure to E. coli LPS. In contrast, treatment with S. minnesota LPS promoted expression of the differentiation marker beta-III-tubulin in U251 cells. The effects on differentiation and stemness were abrogated in presence of Rhodobacter sphaeroides LPS (TLR4 antagonist) or the MyD88-dependent pathway inhibitor IMD0345. These results suggest that depending on the ligand, TLR4-mediated signalling is NF-κB- or IRF3-biased, thereby influencing the cellular behaviour and stemness of U251 cells. Our findings could lead to a better understanding of how glioblastoma cells react to DAMPs and to the development of novel therapeutic options for glioblastoma.

Item Type:Thesis (PhD)
Thesis Supervisor:Widera, D.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:79978

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