Revealing different roles of the mTOR-targets S6K1 and S6K2 in breast cancer by expression profiling and structural analysis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75813 | GEO | 2015/12/09
SECONDARY ACCESSION(S): PRJNA305419
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profiles of ZR751 breast cancer cells after downregulation of S6K1, S6K2 and S6K1+S6K2. Triplicates of control, S6K1siRNA, S6K2siRNA and S6K1+S6K2siRNA, in total twelve samples.
2015-12-09 | E-GEOD-75813 | biostudies-arrayexpress
Project description:To systematically identify the function of S6K1 and S6K2 in glioblastoma cells, LN229 cells were stably transduced with Cas9, control non-targeting sgRNA (sgNT), or sgRNAs targeting S6K1 or S6K2. The cells were then transiently transfected with non-targeting siRNAs (siNT), or siRNA pools targeting S6K1 or S6K2. RNA sequencing was performed to compare cellular responses to inactivation of single or combination S6 kinases.
2024-08-28 | GSE196591 | GEO
Project description:BackgroundThe AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions is emerging. The aim of this work was to explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.Materials and methodsWhole-genome expression profiles were compared for breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.ResultsGenome expression profiles were highly different in S6K1 and S6K2 high tumours, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation lead to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from those of S6K1, facilitating the development of isoform-specific inhibitors. Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.
| S-EPMC4689523 | biostudies-literature
Project description:The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.
| S-EPMC7072743 | biostudies-literature
Project description:Melanoma is often driven by NRAS mutations. Although oncogenic NRAS activates MAPK signaling, inhibition of this pathway has limited efficacy in NRAS-mutant tumors. As there are limited options to treat these tumors, there is a pressing need to identify NRAS-mutant-specific vulnerabilities that can be therapeutically exploited. Metabolic reprogramming is one of the hallmarks of RAS-mutant tumors, creating a dependency on key metabolic pathways. This dependency could be leveraged to combat these tumors. We discovered that abrogation of S6K2, a mTORC1 effector, triggers accumulation of unsaturated fatty acids, lipid peroxidation and cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induced upregulation of S6K1 and PPAR, triggering apoptotic and ferroptosis-like cell death. Conversely, depletion of S6K1 diminished lipid synthesis and cell proliferation, without eliciting cell death. Collectively, our data indicate that a fine balance between S6K1 and S6K2 activity and metabolic homeostasis is required to prompt cell death of NRAS-mutant melanoma. S6K2 is hence a novel therapeutic target for MAPKi-resistant NRAS-mutant melanoma.
2020-03-06 | GSE127916 | GEO
Project description:Targeting S6K1 and S6K2 by siRNA and sgRNA in LN229 GBM cells
| PRJNA805545 | ENA
Project description:Transcriptional analysis of concequent lack of rpS6 kinase activity in mice livers hepatocytes due to deletion of S6 kinases 1 and 2 (S6K1 and S6K2).
2013-01-16 | E-MEXP-3518 | biostudies-arrayexpress
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214340 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214339 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE232448 | GEO