SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE285466 | GEO | 2025/09/05
REPOSITORIES: GEO
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Project description:SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer
| PRJNA1203678 | ENA
Project description:To explore whether creatine regulates iron death sensitivity in colorectal cancer by modulating the function of certain proteins, we performed immunoprecipitation experiments with biotin-labelled creatine and conducted proteomics studies on these IP-down proteins.
2025-09-06 | PXD061637 | Pride
Project description:Creatine is an essential metabolite for the storage and rapid supply of energy in muscle and nerve cells. In humans, the creatine deficiency syndrome (CDS) is manifested by impaired metabolism, transport, and distribution of creatine throughout the body leading to severe forms of mental disabilities. One of the common cause of CDS is mutations that impact the function of the creatine transporter (SLC6A8). This study characterized 30 missense variants of SLC6A8, which include 15 variants of unknown significance and two which were not reported before. These variants were expressed in HEK293 cells, and their subcellular localization and transport activity was assessed. Further, for the first time the interactome of SLC6A8 WT was characterized by quantitative interaction proteomics. Computational methods were then used to first assess the impact of mutations upon the thermodynamic stability of SLC6A8. This was expanded by modeling the impact of mutations upon the inward and outward facing transporter conformation. Next, identified SLC6A8 protein interactions binary complexes were modelled and used to characterize the impact of variants upon the thermodynamic stability of the complexes. This was followed up, by performing for a subset of the variants the interaction proteomics analysis to study changes upon the identified SLC6A8 WT interactome.
2024-01-03 | PXD047111 | Pride
Project description:Background/Objectives: Ferroptosis, an iron-dependent form of cell death, shows promise as a target for therapy-resistant cancers that exhibit increased iron metabolism. Ferroptosis is primarily characterised by lipid peroxidation within cell membranes. However, many cancers evade ferroptosis by upregulation of specialised ferroptosis defence mechanisms. This study investigates ferroptosis susceptibility in Tuberous Sclerosis Complex (TSC) cell models, and ovarian and breast cancer cell lines to identify ferroptosis resistance mechanisms and therapeutic targets. Methods: We assessed ferroptosis susceptibility using the ferroptosis inducers, RSL3 and erastin. We explored ferroptosis resistance genes using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA-sequencing was conducted to identify dysregulated ferroptosis resistance genes and to better characterise NRF2 target genes. RNA sequencing was also performed to identify gene expression after treatment with pro-ferroptotic iron-oxide nanoparticles. Results: TSC2-deficient cells exhibited resistance to RSL3 and erastin-induced ferroptosis, which correlated with increased ferroptosis defence gene expression, including NRF2 and downstream targets. NRF2 inhibition re-sensitised TSC2-deficient cells to ferroptosis, confirming its protective role. However, FSP1 inhibition did not re-sensitise TSC2-deficient angiomyolipoma kidney tumor cells to RSL3. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cell lines. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition in reversing ferroptosis resistance. Conclusions: Our findings highlight NRF2 and FSP1 as key regulators of ferroptosis resistance in TSC2-deficient and cancer cells. However, the differential efficacy of targeting these pathways suggests that patient stratification may be necessary for optimal therapeutic strategies. Targeting NRF2 and FSP1 could enhance ferroptosis susceptibility, offering a potential therapeutic approach for ferroptosis resistance cancers.
2025-07-14 | GSE300960 | GEO
Project description:Ferroptosis therapy has been well-established in various cancers; however, colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the use of ferroptosis therapy in CRC. Through drug screening, we found histone deacetylase inhibitor (HDACi) significantly sensitized ferroptosis. Mechanically, HDACi reduced FSP1 by promoting its mRNA degradation, a known ferroptosis defense molecular. In further research, we confirmed that HDACi specifically targeted HDAC1 and suppressed the H3K27ac modification of FTO and ALKBH5. The activation of FTO and ALKBH5 resulted in a reduction of N6-methyladenosine (m6A) modification on FSP1 mRNA, leading to its degradation and ultimately sensitizing CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically reduced CRC both in vivo and in vitro. In conclusion, our research reveals how HDACi sensitized ferroptosis and prompts the combination of HDACi/ferroptosis inducers as a promising therapeutic strategy for solid tumors.
2025-04-03 | GSE263463 | GEO
Project description:Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.
2023-03-14 | GSE216766 | GEO
Project description:Mutations in the X-linked solute carrier family 6-member (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with cognitive dysfunction, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood and this lack of knowledge might hinder the development of therapeutic strategies. Here, we show that Cr deficiency perturbs gene expression in excitatory neurons, inhibitory cells and oligodendrocytes, inducing a remodeling of circuit excitability and synaptic wiring, while no effects are present in astrocytes and endothelial cells. We also describe specific alterations of high-energy demanding, Parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional phenotype, affecting initiation, kinetics and frequency of action potentials. Mice lacking Slc6a8 only in PV+ neurons recapitulate numerous CTD features, such as cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ cells is sufficient to determine the CTD neurological endophenotype. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses induces a significant improvement of cortical activity in Slc6a8 knock-out animals. Altogether, these data establish that Slc6a8 is critical for the normal function of PV+ interneurons and that a subtle dysfunction of these cells is critical for the disease pathogenesis, suggesting a novel therapeutic venue for CTD.
2023-06-01 | GSE218797 | GEO
Project description:Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. We find that the creatine transporter solute carrier family 6, member 8 (SLC6A8) is upregulated in hypoxic HCC cells. Hypoxia-induced creatine accumulation drives metabolic reprogramming and antagonizes parthanatos. Pharmacological inhibition of SLC6A8 represents a promising therapeutic strategy for HCC.
2025-07-23 | GSE289804 | GEO
Project description:ERK2-dependent gene expression
| PRJNA514405 | ENA
Project description:We employed genetic mouse model (Fsp1-Cre;Col1a1flox/flox) to delete Col1a1 (type I collagen) specifically in Fsp1-expressing cells in comparison with control WT mice (Cre-negative;Col1a1flox/flox). Single-cell RNA-sequencing analyses were performed on unfractionated live cell mixtures from bone marrow samples from Fsp1-Cre;Col1a1flox/flox mice and WT mice, to investigate the impact of Fsp1-cell-specific Col1 deletion on bone marrow microenvironment.
2021-09-18 | GSE184360 | GEO