Cancer cell stiffening via CoQ10 and UBIAD1 regulates ECM signaling and ferroptosis resistance in Breast Cancer
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ABSTRACT:
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: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: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.
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Project description:CoQ10 (Coenzyme Q10) is an essential fat-soluble metabolite that plays a key role in cellular metabolism. A less-known function of CoQ10 is whether it may act as a plasma membrane-stabilizing agent and whether this property can affect cancer development and progression. Here, we show that CoQ10 and its biosynthetic enzyme UBIAD1 play a critical role in plasmamembrane mechanical properties that are of interest for breast cancer (BC) progression and treatment. CoQ10 and UBIAD1 increase membrane fluidity leading to increased cell stiffness in BC. Furthermore, CoQ10 and UBIAD1 states impair ECM (extracellular matrix)-mediated oncogenic signaling and reduce ferroptosis resistance in BC settings. Analyses on human patients and mouse models reveal that UBIAD1 loss is associated with BC development and progression and UBIAD1 expression in BC limits CTCs (circulating tumor cells) survival and lung metastasis formation. Overall, this study reveals that CoQ10 and UBIAD1 can be further investigated to develop therapeutic interventions to treat BC patients with poor prognosis.
| S-EPMC11410950 | biostudies-literature
Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
2021-10-09 | GSE160574 | GEO
Project description:Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with increasing incidence and mortality rates. Resistance to cell death is a hallmark of cancer, and ferroptosis, a form of non-apoptotic cell death, has emerged as a critical factor in tumor suppression. The RNA-binding protein IGF2BP3, which plays a significant role in colon cancer progression, has been shown to modulate various oncogenic processes. However, its involvement in ferroptosis regulation in colon cancer remains largely unexplored. This study investigates the role of IGF2BP3 in ferroptosis regulation and its potential as a therapeutic target in colon cancer. Our data show that IGF2BP3 is upregulated in colon cancer tissues and correlates with poor prognosis. Knockdown of IGF2BP3 in colon cancer cell lines enhances sensitivity to ferroptosis induction, evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, which are reversed by the ferroptosis inhibitor ferrostatin-1. Mechanistically, IGF2BP3 regulates ferroptosis by stabilizing SLC7A11 mRNA, a key ferroptosis regulator, through its interaction with the mRNA. Additionally, miR-98-5p directly targets IGF2BP3, enhancing ferroptosis sensitivity. In vivo studies confirm that IGF2BP3 knockdown suppresses tumor growth, highlighting its potential as a therapeutic target. Overall, our findings suggest that IGF2BP3 plays a pivotal role in regulating ferroptosis in colon cancer, offering new avenues for therapeutic strategies in colon cancer treatment.
2025-02-21 | GSE289758 | GEO
Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
2025-03-19 | GSE290270 | GEO
Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
2025-03-19 | GSE290271 | GEO
Project description:Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are comprised of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.
2025-07-08 | GSE301773 | GEO