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1.
Int J Mol Sci ; 24(21)2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37958846

ABSTRACT

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with few effective treatment strategies. The research on the development of new treatments is often constrained by the limitations of preclinical models, which fail to accurately replicate the disease's essential characteristics. Herein, we describe the obtention, molecular, and functional characterization of the GBM33 cell line. This cell line belongs to the GBM class according to the World Health Organization 2021 Classification of Central Nervous System Tumors, identified by methylation profiling. GBM33 expresses the astrocytic marker GFAP, as well as markers of neuronal origin commonly expressed in GBM cells, such as ßIII-tubulin and neurofilament. Functional assays demonstrated an increased growth rate when compared to the U87 commercial cell line and a similar sensitivity to temozolamide. GBM33 cells retained response to serum starvation, with reduced growth and diminished activation of the Akt signaling pathway. Unlike LN-18 and LN-229 commercial cell lines, GBM33 is able to produce primary cilia upon serum starvation. In summary, the successful establishment and comprehensive characterization of this GBM cell line provide researchers with invaluable tools for studying GBM biology, identifying novel therapeutic targets, and evaluating the efficacy of potential treatments.


Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Glioblastoma/metabolism , Brazil , Brain Neoplasms/metabolism , Cell Line, Tumor , Tubulin/metabolism
2.
Mol Oncol ; 14(1): 159-179, 2020 01.
Article in English | MEDLINE | ID: mdl-31701625

ABSTRACT

The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in nontumoral brain (NB) and grade I-IV gliomas. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (GBMs) that excluded long-survivor cases expressed higher levels of RSK1 (RSK1hi ). No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2hi ) were associated with worse survival. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBM demonstrating the lowest RSK3 protein levels. RSK1hi and, to a lesser extent, RSK2hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration suggest RSK1 as a potential progression marker and therapeutic target for gliomas.


Subject(s)
Brain Neoplasms/metabolism , Glioma/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Membrane Proteins/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Transcriptome/immunology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Brain Neoplasms/mortality , Databases, Genetic , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Glioblastoma/genetics , Glioblastoma/metabolism , Glioma/genetics , Glioma/immunology , Glioma/secondary , Humans , Immunohistochemistry , Killer Cells, Natural/metabolism , Macrophages/metabolism , Membrane Proteins/genetics , Neoplasm Grading , Phosphorylation , Protein Isoforms , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Transcriptome/genetics
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