Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis resistance in Breast Cancer
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PROVIDER: PRJNA955830 | ENA |
REPOSITORIES: ENA
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Project description:Here, we discovered that CoQ10 and its biosynthetic enzyme UBIAD1 play a critical role in plasma membrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. In detail, CoQ10 and UBIAD1 increased membrane fluidity leading to increased cell stiffness in BC. High UBIAD1/CoQ10 states impair lipid rafts and ECM-mediated oncogenic signaling and reduce the ferroptosis resistance of BC cells. Furthermore, analyses on BC patients and BC mouse models reveal that UBIAD1 loss is associated with BC development and progression. UBIAD1 expression in aggressive BC limits CTCs survival and lung metastasis formation in experimental xenograft assays.
2024-07-23 | GSE229792 | GEO
Project description:Cartilage aging is a quintessential feature of knee osteoarthritis, and extracellular matrix (ECM) stiffening is a typical feature of cartilage aging. However, the mechanism of ECM stiffening to influence chondrocytes and downstream molecules is still poorly understood. Here, we mimicked the physiological and pathological stiffness of human cartilage by using polydimethylsiloxane-based substrates. We show that the epigenetic regulation of Parkin by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiff matrix affects the physiology of chondrocytes. We found that ECM stiffening could accelerate the senescence of cultured chondrocytes in vitro, and also found that stiff ECM downregulated HDAC3, drove Parkin acetylation to activate excessive mitophagy, and accelerated chondrocyte senescence and osteoarthritis in mice. In contrast, intra-articular injection of adeno-associated virus expressing HDAC3 restored the young phenotype of aged chondrocytes stimulated by ECM stiffening and alleviated osteoarthritis in mice. Our findings indicate that changes in the mechanical properties of ECM initiate pathogenic mechanotransduction signals, promote the acetylation of Parkin and hyperactivate mitophagy, and damage the health of chondrocytes. These findings may provide new insights into how the mechanical properties of ECM regulate chondrocytes.
2024-06-16 | PXD046993 | Pride
Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240526 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240525 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.
2025-12-05 | GSE240524 | GEO
Project description:Increased extracellular matrix (ECM) and matrix stiffness promote solid tumor progression. However, mechanotransduction in cancers arising in mechanically active tissues remains underexplored. Here, we report upregulation of multiple ECM components accompanied by tissue stiffening in vocal fold cancer (VFC). We compare non-cancerous (NC) and patient-derived VFC cells – from early (mobile, T1) to advanced-stage (immobile, T3) cancers – revealing an association between VFC progression and cell-surface receptor heterogeneity, reduced laminin-binding integrin cell-cell junction localization and a flocking mode of collective cell motility. Mimicking physiological movement of healthy vocal fold tissue (stretching /vibration), decreases oncogenic nuclear β-catenin and YAP levels in VFC. Multiplex immunohistochemistry of VFC tumors uncovered a correlation between ECM content, nuclear YAP and patient survival, concordant with VFC sensitivity to YAP-TEAD inhibitors in vitro and in vivo. Our findings present evidence that VFC is a mechanically sensitive malignancy and restoration of tumor mechanophenotype or YAP/TAZ targeting, represents a tractable anti-oncogenic therapeutic avenue for VFC.
2025-11-25 | GSE297099 | GEO
Project description:KRAS mutation activates multiple intracellular signalling pathways, leading to tumour development and progression. However, whether KRAS mutations are involved in regulating ferroptosis in cancer and the underlying mechanism remains unclear. Here, we constructed stable KRASWT and KRASG12D-mutant cell lines by transfecting wild-type (WT) or G12D plasmids into original KRAS WT cells and detected their cell viability under the treatment of ferroptosis inducer RSL3 or erastin. We found compared with WT cells, KRASG12D-mutated pancreatic and colorectal cancer cells presented greater viability and less cell death, along with lower levels of lipid peroxidation (LPO) and fewer damaged mitochondria, suggesting that the G12D mutation confers resistance to ferroptosis. Moreover, we found that KRASG12D mutated cancer cells demonstrated increased glycolysis and elevated lactate production, which was dependent on MEK-ERK-mediated L-lactate dehydrogenase A (LDHA) phosphorylation. Importantly, lactate supplementation in WT cells also resulted in ferroptosis resistance, indicating that G12D mutation-induced resistance to ferroptosis may be linked to lactate production. Mechanistically, G12D mutation-derived lactate accumulation induces Glutamate-cysteine ligase modifier (GCLM) lactylation, a process catalysed by Acetyl-CoA Acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of Glutamate-cysteine ligase (GCL) and suppressed Glutathione (GSH) synthesis. Ultimately, we found that ACAT2 knockdown can overcomes ferroptosis resistance in G12D-mutated cancer models in vivo. Thus, our study reveals a novel role for the G12D mutation in regulating GCLM lactylation and ferroptosis. Targeting GCLM lactylation may represent a promising strategy for overcoming ferroptosis resistance.
2025-05-07 | PXD062451 | Pride
Project description:Triggering ferroptosis has recently been demonstrated to be a promising approach for cancer treatment. However, the application of current ferroptosis inducers, such as GPX4 inhibitors, was rather limited due to their pharmaceutical or safety issues, which evoking the discovery of new favorable candidates. In this study, we took advantage of a phenotypic screening strategy and discovered (20S)-Protopanaxatriol (hereafter as (20)S-APPT), a derivative of ginsenosides, as a novel ferroptosis inducer both in vitro and in vivo, with desirable safety in particular. Mechanistic investigations revealed that (20)S-APPT induces ferroptosis by targeting plasma-membrane localized CoQ10 oxidoreductase FSP1. Upon FSP1 inhibition, oxidation of arachidonic acid in an ACSL4 dependent way as well as reactive oxygen species produced by mitochondrial oxidative stress are both involved to boost the process of ferroptosis. Intriguingly, we firstly uncovered that inhibition of FSP1 alone is sufficient to induce ferroptotic cell death in a subset of liver and bile duct cancer cells. Furthermore, we unexpectedly found that only the addition of GCS inhibitor BSO, which attenuates intracellular GSH, exerts synergistic effect to induce ferroptosis with FSP1 inhibitors in rest non-responsive cancer cells, while sparing normal cell counterparts intact. Overall, our work helped to gain insights into a new ferroptotic role of FSP1 and further proposed that co-targeting FSP1 and GCS is a hopeful and safe strategy to combat liver and bile duct cancer through triggering ferroptosis, which might facilitate to pave a new way for drug development and further clinical therapeutic intervention in the future.
2025-12-09 | GSE284669 | GEO
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:Tissue stiffening is a physical hallmark of solid tumor. In our study, we found that the mechanosensitive ion channel PIEZO1 can be tumor cells force sensor and transducer that regulate the altered tissue mechanics. We examined the transcriptional changes modulated by depletion of PIEZO1 in two human GBM cell lines. We found that with PIEZO1 KD, the components involved in ECM organization, focal adhesion formation, cytoskeleton, and mitosis, which contribute to tissue stiffness, are down-regulated.
2018-10-18 | GSE113261 | GEO