Aberrant expression of RSK1 characterizes high‐grade gliomas with immune infiltration

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 (RSK1 hi). No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2 hi) 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. RSK1 hi and, to a lesser extent, RSK2 hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1 hi 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 RSK1 hi 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

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

“…RPS6KA1 belongs to the family of the ribosomal protein S6 kinase (RPS6K) ( Li et al, 2012 ; Czaplinska et al, 2018 ). The RPS6K family is reported to be involved in a lot of pathways, which are important for tumor occurrence and progression ( Hajj et al, 2020 ; Lai et al, 2020 ; Yang et al, 2020 ). A new study indicates that RPS6KA1 is a potential target of new treatment strategies for drug-resistant AML patients with FLT3-ITD mutation, especially combining PI3K, PIM, or Bcl-2 family members ( Watanabe et al, 2019 ).…”

Signal Pathways Involved in the Interaction Between Tumor-Associated Macrophages/TAMs and Glioblastoma Cells

“…In an independent cohort, Glaucia et al. confirmed that RSK1hi GBMs excluded long survivors, and RSK1 expression was positively associated with the protein level of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with the TAM-associated CD68 ( 69 ). Tao et al.…”

From Neural Stem Cells (NSC) to Glioblastoma (GBM): A Natural History of GBM Recapitulated in Vitro

“…Interestingly, although, both RSK1 and RSK2 are associated with glioma malignity, RSK1 has been described as a potential progression marker and a therapeutic target for gliomas. In fact, RSK1 phosphorylation levels (Ser380), which more specifically reveals ER K activation, are higher in GBM [24]. Additionally, RSK1 phosphorylates p27 at Thr198, leading to accumulation of phosphorylated p27 in the cytoplasm [25].…”