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| Full text | |
| Author(s): |
Moretti, Isabele F.
[1]
;
Lerario, Antonio M.
[2]
;
Trombetta-Lima, Marina
[1]
;
Sola, Paula R.
[1]
;
Soares, Roseli da Silva
[1]
;
Oba-Shinjo, Sueli M.
[1]
;
Marie, Suely K. N.
[1]
Total Authors: 7
|
| Affiliation: | [1] Univ Sao Paulo, Fac Med FMUSP, Dept Neurol, Lab Mol & Cellular Biol LIM15, Sao Paulo, SP - Brazil
[2] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | SCIENTIFIC REPORTS; v. 11, n. 1 JAN 14 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients. (AU) | |
| FAPESP's process: | 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine |
| Grantee: | Berenice Bilharinho de Mendonça |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 16/14695-9 - Toll Like Receptor 4 role in glioblastoma cell lineages |
| Grantee: | Isabele Fattori Moretti |
| Support Opportunities: | Scholarships in Brazil - Master |
| FAPESP's process: | 15/26328-8 - Comparative analysis of the Reck tumor suppressor gene role in glioblastoma stem cell sub-population and in normal neural stem cells. |
| Grantee: | Marina Trombetta Lima |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 04/12133-6 - Search for molecular markers related to the diagnosis and prognosis of tumors of the central nervous system |
| Grantee: | Suely Kazue Nagahashi Marie |
| Support Opportunities: | Research Projects - Thematic Grants |