Cell Death & Disease最新文献

Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI). In this study, we demonstrated that the conditional knockout of eukaryotic initiation factor 2 (eIF2) subunits Eif2s1 and Eif2s2 in mouse oocytes caused oocyte apoptosis within the early growing follicles. Subsequent research indicated that the depletion of Eif2s2 in oocytes reduced the levels of mitochondrial fission-related proteins (p-DRP1, FIS1 and MFF) and increased the mRNA and protein levels of the integrated stress response (ISR)-related factors (ASNS, SLC7A1, GRB10 and PSAT1). Consistent with this, the depletion of Eif2s2 in oocytes resulted in mitochondrial dysfunction characterized by elongated form, aggregated distribution beneath the oocyte membrane, decreased mitochondrial membrane potential and ATP content, and excessive accumulation of reactive oxygen species (ROS). At the same time, the depletion of Eif2s2 in oocytes led to increased levels of DNA damage response proteins (γH2AX, p-CHK2 and p53) and proapoptotic proteins (BAX and PARP1), as well as decreased the levels of anti-apoptotic protein BCL-xL. Collectively, these findings indicate that the depletion of eIF2 subunits in mouse oocytes leads to oocyte apoptosis within the early growing follicles, attributed to the impaired translation of mitochondrial dynamics regulatory proteins and then the upregulated ROS levels and DNA damage. This study provides new insights into pathogenesis and genetic diagnosis for POI.

Treatment-resistant glioblastoma stem and precursor cells (GPCs) drive glioblastoma (GBM) growth and recurrence. Thus, targeting the molecular machinery that sustains GPCs in an undifferentiated and self-renewing state is a promising therapeutic strategy. The transcription factor SOX21 effectively suppresses the tumorigenic capacity of GPCs, but the mechanism by which SOX21 impedes GPC features is unknown. By engineering patient-derived GPCs with a transgenic TetOn system we show that SOX21 expression induces an anti-tumorigenic transcriptional program, aligning with clinical data demonstrating a positive correlation between SOX21 levels and improved GBM patient survival. Induced SOX21 expression in GPCs within pre-established GBM reduces their capacity to sustain tumor growth and significantly extends the survival of the orthotopically transplanted mice. Mechanistically, SOX21 functions as a tumor suppressor by binding a large set of AP-1-targeted chromatin regions, leading to epigenetic repression of AP-1-activated genes. Consistently, the anti-tumorigenic activities of SOX21 are largely replicated by AP-1 inhibitors, which decrease GPC proliferation and survival, while overexpression of the AP-1 family member, c-JUN, counteracts these effects. Our findings identify SOX21 as a key regulator that prevents GPC malignancy by targeting and repressing an AP-1-driven, tumor-promoting gene expression program. These results highlight SOX21-regulated pathways as promising therapeutic targets for GBM.

Despite recent medical advances, colorectal cancer (CRC) remains the second-leading cause of cancer-related death worldwide. For patients with KRAS wild-type metastatic CRC, the monoclonal antibody cetuximab, which targets the epidermal growth factor receptor (EGFR), is an approved treatment option. However, therapeutic success is often limited by the emergence of drug-resistant cancer cell populations within a few months. Therefore, alternative strategies to effectively target cetuximab-refractory CRC are urgently needed. Here, we sought to identify second-line therapeutic strategies using a CRC cell line with acquired cetuximab resistance as a model. Transcriptomic profiling of the resistant cells identified the apoptosis pathway as a potential therapeutic target, which was supported by their increased susceptibility to BH3-mimetics targeting the anti-apoptotic proteins MCL-1 and BCL-xL under both 2D and 3D culture conditions. These findings were validated in organotypic CRC slice cultures generated from cetuximab-resistant patient-derived xenografts (PDXs). Multiplex immunofluorescence staining demonstrated that BCL-xL inhibition effectively triggered apoptosis in heterogeneous PDX tumor slice models, including models harboring oncogenic BRAF mutations. Our findings suggest that cetuximab-resistant CRC retains apoptotic competence, and that BCL-xL inhibition serves as a robust alternative therapeutic strategy that is largely independent of the tumor mutational profile.

TDP-43 dysfunction is thought to be central to ALS pathogenesis. Studying mutations in the gene which encodes TDP-43, TARDBP, provides a valuable opportunity to gain insight into how TDP-43 dysfunction alters cellular homoeostasis. Our group has previously developed a TDP-43^M337V mouse embryonic stem cell-derived motor neuron (mESC-MN) model, which expresses a single copy of the human TARDBP gene expressing the pathogenic M337V mutation at low levels. Here, we perform extensive phenotypic characterisation of this model, and show that TDP-43^M337V leads to reduced MN viability, impaired axonal transport and reduced basal glycolysis compared to TDP-43^WT controls. Altered neuronal viability and function occurs in the absence of TDP-43 mislocalisation or aggregation, suggesting 'proteinopathy' is downstream of these ALS-relevant phenotypes. These findings provide further support for a link between TDP-43 dyshomeostasis, cellular bioenergetics and axonal transport and suggest these pathways warrant further investigation as targets for therapeutic intervention.

The association between folate metabolism abnormalities and the development of colorectal cancer (CRC) remains controversial. Here, we report that the folate exerts a tumor-suppressive role in CRC; however, the manifestation of this effect is restricted by the expression level of folate transporter SLC46A1 in CRC cells. Multi-cohort profiling revealed significant downregulation of SLC46A1 in CRC tissues compared to adjacent normal tissues, where low expression independently predicted poor overall survival. Functional studies demonstrated that SLC46A1-mediated folate uptake suppressed tumor proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, SLC46A1 deficiency restricted intracellular folate availability and impaired cellular methylation potential, as evidenced by a reduced SAM/SAH ratio, leading to DNA hypomethylation at specific sites such as the FOS proto-oncogene promoter. This epigenetic reprogramming triggers transcriptional activation of key oncogenic effectors CCND1, BCL2, and PLAU involved in CRC progression. Clinically, we found a significant inverse correlation between SLC46A1 expression and folate levels in tumor interstitial fluids of CRC, suggesting impaired folate uptake in low SLC46A1 tumors. Multi-color immunofluorescence across two cohorts further demonstrated conserved inverse associations between SLC46A1 and FOS expression in primary tumors and metastatic lesions. This study elucidates the molecular mechanism by which folate inhibits CRC progression through the "SLC46A1-epigenetic-transcriptional regulation" axis, providing mechanistic insights into folate deficiency-driven CRC progression and biomarkers for precision CRC intervention. This study elucidates the tumor-suppressive role of the folate transporter SLC46A1 in CRC. In normal cells, SLC46A1 facilitates folate uptake, supporting one-carbon metabolism and maintaining genomic stability. In CRC, however, SLC46A1 downregulation induces intracellular folate deficiency, triggering locus-specific DNA hypomethylation at the FOS promoter, which activates oncogenic transcription of key downstream effectors (CCND1, BCL2, PLAU), driving tumor progression. The graphical abstract illustrates the differential impact of SLC46A1 on folate metabolism and gene expression in normal versus tumor cells, highlighting its potential as a therapeutic target in CRC.

Ewing sarcoma (EWS) is a highly aggressive pediatric malignancy characterized by elevated expression of SLFN11, which impairs DNA repair by binding to and functionally inhibiting DNA repair complexes, thereby enhancing susceptibility to genotoxic therapies. However, relapse remains a major clinical challenge and is often accompanied by the emergence of therapeutic resistance linked to reduced SLFN11 expression. We hypothesized that SLFN11-deficient tumors undergo adaptive metabolic reprogramming to overcome chemosensitivity. Here, we leverage transcriptomic and metabolomic profiling in patient-derived EWS models to demonstrate that SLFN11 loss drives downregulated mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) expression, higher accumulation of glycerol-3-phosphate, fatty acid unsaturation, and enhanced glycerophospholipid (GPL) biosynthesis. Subsequently, targeting GPL biosynthesis (FSG67) restored DNA-damaging agent (SN-38) sensitivity in SLFN11-deficient EWS model, revealing a potential metabolic vulnerability to overcome chemoresistance. Furthermore, SLFN11 knockout tumors exhibited an elevated phosphocholine/glycerophosphocholine ratio, offering a potential non-invasive diagnostic biomarker.

Glioblastoma (GBM) acquires malignant traits through complex molecular adaptations that sustain immune evasion, often characterized by hypoxia and overexpression of the phagocytosis checkpoint CD47. However, the role of hypoxic drivers coordinating CD47-dependent immune evasion remains poorly defined. Here, we integrated single cell RNA sequencing and proteomic analysis to identify that insulin-like growth factor binding protein 2 (IGFBP2) was co-expressed with CD47 in hypoxic mesenchymal-like GBM subpopulations, synergistically promoting tumor progression and immune evasion. Mechanically, hypoxia induced IGFBP2 expression via HIF-2α-mediated transcriptional activation and further increased IGFBP2-positive exosome secretion through HIF-1α-dependent RAB3A upregulation. Moreover, IGFBP2 was predominantly localized on the exosome surface via integrin α5β1 and activated integrin/FAK/STAT3 signaling to enhance CD47 expression and inhibit macrophage phagocytosis. Clinically, serum exosomal IGFBP2 levels correlated with tumor grade and could serve as a diagnostic biomarker. Importantly, combinatorial blockade of IGFBP2 and CD47 synergistically suppressed tumor growth and prolonged survival in orthotopic GBM models. Together, our findings uncovered the hypoxia-exosomal IGFBP2-CD47 axis in GBM immune evasion and provided a compelling rationale for combination therapy to improve immunotherapy efficacy in GBM.

Photoreceptors (PRs) are specialized light-sensitive cells responsible for vision, and their death is the primary cause of retinal degeneration and vision loss. Recent studies using cells such as HeLa and PC12 have demonstrated cellular recovery even from late stages of apoptosis. Here, we demonstrate for the first time that PR cells can recover from features of apoptosis following exposure to apoptotic stressors. Upon apoptotic stimuli (staurosporine or hypoxia), 661 W cells, a murine cone PR cell line, exhibited morphological and functional features of apoptosis, such as rounding and blebbing, caspase-3 activation, PARP cleavage, and phosphatidylserine externalization. These processes were reversed upon the alleviation of stress. We also observed that mitochondrial function is central to apoptotic recovery of photoreceptor cells, as evidenced by the restoration of intracellular ATP levels and reduction in mitochondrial reactive oxygen species (mROS). Mitophagy was demonstrated to play a crucial role in cell survival, with increased protein and mRNA expression of mitophagy markers during recovery from apoptosis. Furthermore, the modulation of mitophagy confirmed its protective role in the recovery phase, as its induction with MF-094 reduced apoptosis while its inhibition with Mdivi-1 exacerbated cell death. In vivo, we demonstrate the recovery of PRs from apoptosis using an experimental model of transient retinal detachment. Altogether, the findings of this study indicate that PR cells can recover from entry into the apoptotic cascade, and that mitophagy is essential for apoptotic recovery in these cells.

IF1 is the natural inhibitor of the mitochondrial ATP synthase during hydrolytic activity. It has been found to be overexpressed in many tumors, where it acts as a pro-oncogenic protein. During oxidative phosphorylation, IF1 binds to a novel site on the OSCP subunit of ATP synthase and promotes tumorigenesis by protecting cancer cells from permeability transition pore (PTP)-dependent apoptosis. In this work, honokiol, a biphenolic compound, showed binding affinity for two sites on the OSCP subunit, as predicted by molecular docking analysis. It was shown to be effective in disrupting the IF1-OSCP interaction and sensitizing cancer cells to apoptosis. In vivo, xenografts of zebrafish injected with IF1-expressing HeLa cells showed tumor development. The same xenografts, treated with honokiol, showed a significant reduction in tumor mass, similar to untreated fish injected with IF1 KO HeLa cells. In vitro, honokiol inhibits colony formation in soft agar of IF1-expressing HeLa cells by promoting the PTP opening and cell death, without any effect on cell proliferation. Interestingly, honokiol was shown to block metastasis in fish xenografts and migration in a wound healing assay, by promoting mitochondrial swelling in both control and IF1 KO cell lines, when cells are moving to close the scratch area. In conclusion, honokiol appears to be a promising anti-cancer compound, with pro-apoptotic properties through the displacement of IF1 from the OSCP subunit of ATP synthase, and anti-metastatic effects that are due to mitochondrial PTP opening.

Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.