Cell Death Discovery最新文献

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of cancer-related death worldwide. The prognosis is poor, with a median survival of 12-15 months in patients with advanced-stage disease. Early diagnosis and the development of new, more effective therapeutic strategies are needed to address the challenges posed by this malignancy. Although immune checkpoint inhibitors have replaced multikinase inhibitors as first-line therapy, sorafenib continues to represent a valuable option for patients with contraindications to newer treatments. Based on genome-wide RNA-seq analysis, which identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver cancer models. Co-treatment with SR9009 and sorafenib significantly enhanced cytotoxic effects in both mouse and human liver cancer cells. This synergistic activity was associated with increased levels of free heme and a complete inhibition of mitochondrial OxPhos. In vivo xenograft studies confirmed that the combination was effective even in sorafenib-resistant tumors. Furthermore, in a N-Nitrosodiethylamine (DEN)-induced HCC model, the combination therapy led to a reduction in size in over 90% of tumor nodules, representing a significant improvement over sorafenib alone. The combination was well tolerated, with no evident signs of acute toxicity. These findings support the concept that the efficacy of anticancer therapies can be enhanced by targeting the metabolic adaptations that tumor cells rely on for survival. Combining sorafenib with agents like SR9009, that disrupt metabolic homeostasis, may offer a promising strategy for treating advanced HCC.

The testicular microenvironment, with Sertoli cells as a key component, plays a pivotal role in spermatogenesis. DHX37, a member of the DEAH-box family of RNA helicases, has been identified as a pathogenic gene in 46, XY disorders of sex development (DSD), underscoring its potential significance in testicular development. Here, we focus on elucidating the role of Dhx37 in maintaining Sertoli-cell survival. RIP-seq and RNAi-RNA-seq reveal that Dhx37 safeguards nucleolar integrity and PI3K-AKT signaling, suppresses p53-driven apoptosis, and its loss triggers pro-apoptotic splicing. Cell-specific Dhx37 knockout mice (Dhx37^-/-) were subsequently generated to investigate the function of Dhx37 in testicular development. In the Dhx37^-/- mice, we observed pronounced defects, including diminished testicular volume, lower testosterone levels, and marked vacuolization of the seminiferous tubules. Immunofluorescence staining revealed disruptions in both Sertoli and germ cell compartments, characterized by reduced cell proliferation and elevated apoptosis. The snRNA-seq disclosed marked changes in the expression of genes governing apoptosis and proliferation, findings that were further validated through qRT-PCR and Western blotting. In this study, we identified Dhx37 as a pivotal determinant of nucleolar architecture in murine testicular Sertoli cells. Preservation of the nucleolus safeguards supporting normal testicular morphogenesis. Graphical Abstract Schematic illustrating the proposed mechanisms by which Dhx37 deficiency affects testicular development and spermatogenesis. In normal testes (left), Sertoli cells maintain a well-organized nucleolus with intact nucleolar structures, including Granular Component (GC), Fibrillar Center (FC), Dense Fibrillar Component (DFC). In this context, MDM2 interacts with P53, preventing the accumulation of P53 and inhibiting apoptosis, thereby supporting normal testicular architecture and spermatogenesis. However, in Dhx37^-/- mice (right), testicular volume is reduced, and seminiferous tubules undergo atrophy due to nucleolar stress in Sertoli cells. The disruption of nucleolar structure leads to the export of FBL from the nucleolus, where it binds to MDM2. This disruption is accompanied by downregulation of key factors in the PI3K pathway (Fgf2, Lpar2, PI3KR2, PI3KR5) and upregulation of the P53 pathway, culminating in apoptosis. As a result, Dhx37 deficiency impairs Sertoli cell function, leading to a failure in supporting testicular development and spermatogenesis. Created with BioGDP.com.

Radiation resistance is the major cause of non-small cell lung cancer (NSCLC) treatment failure. Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to radiotherapy in NSCLC. However, the mechanisms of HR repair in radiation resistance remains unclear. In this study, we investigated the functional role of the transcription factor Spermatogenesis and oogenesis basic helix-loop-helix transcription factor 2 (SOHLH2) in NSCLC HR repair and radioresistance. Our research unveiled that the expression levels of SOHLH2 increased in NSCLC compared with adjacent non-tumor tissues. Elevated SOHLH2 expression promotes NSCLC cell proliferation and radiation resistance, while knocking down SOHLH2 has the opposite effect. Mechanistically, SOHLH2 transcriptionally activated the expression of RAD54L, thereby promoting HR repair and the survival of cancer cells in response to radiation. Notably, RAD54L overexpression was able to rescue the suppression of NSCLC HR repair and radioresistance induced by SOHLH2 knockdown. Therefore, SOHLH2-RAD54L axis may serve as a potential therapeutic target for overcoming radioresistance in NSCLC.

Ovarian cancer remains one of the most lethal gynecologic malignancies due to late diagnosis, limited treatment options, and frequent chemoresistance. Docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid, has been associated with anti-tumor effects in various cancer models. Here, we investigated the effects of DHA on cell death, oxidative stress, and mitochondrial function in A2780 human ovarian cancer cells. Our data show that DHA decreases cell viability and proliferation in a dose- and time-dependent manner, promoting lytic cell death with increased membrane permeability and LDH release. We identified pyroptosis as the predominant death mechanism, evidenced by caspase-1 activation, pore formation, and mitochondrial dysfunction. DHA treatment rapidly increased intracellular reactive oxygen species (ROS) and mitochondrial superoxide levels, which were essential for both membrane pore formation and the loss of mitochondrial membrane potential. Notably, ROS scavenging with N-acetylcysteine reversed DHA-induced mitochondrial damage and pyroptosis, indicating ROS dependence. Furthermore, DHA reduced mitochondrial content and impaired spare respiratory capacity, suggesting disrupted mitochondrial adaptability. Caspase-1 inhibition restored both mitochondrial integrity and respiratory function, highlighting a mechanistic role for caspase-1 in mediating DHA-induced bioenergetic dysfunction. Collectively, our findings reveal that DHA compromises ovarian cancer cell survival by triggering ROS- and caspase-1-dependent pyroptosis and mitochondrial dysfunction. This study expands the understanding of DHA's anti-cancer mechanisms and positions it as a promising candidate for adjuvant therapies targeting mitochondrial vulnerabilities and immunogenic cell death pathways in ovarian cancer.

Emerging evidence revealed an association between perfluorooctanoic acid (PFOA) exposure and reduced bone mass density, leading to osteoporosis disease. This confirms the bone as a target tissue for per- and polyfluoroalkyl substances (PFAS). However, it is still unclear during which phase, proliferation or differentiation, PFOA exerts the most significant harm on osteoblasts, the cells responsible for secreting bone matrix. To tackle the intriguing question of how PFOA treatment affects the process, this study investigated the impact of different concentrations of PFOA on 2D and 3D human fetal osteoblast (hFOB1.19) cell line cultures representing the proliferation and differentiation phases, respectively. In 2D cultures, a 6-day PFOA exposure impaired antioxidant defense without directly altering osteogenesis or calcium deposition. In 3D spheroids, PFOA disrupted spheroid morphology and the deposition of the organic component of extracellular matrix (ECM) in a time-dependent manner. Given the relevance of the endocannabinoid system (ECS) in bone remodeling, we further assessed cannabinoid receptor 1 (CB1) levels. In 2D cultures, 10 µM PFOA reduced CB1 protein levels in parallel with decreased collagen levels. Conversely, in 3D spheroids, exposure to 100 µM PFOA for 2 days significantly increased CB1 levels while reducing the levels of degraded collagen. These findings emphasize the non-monotonic, phase- and time-dependent effects of PFOA on osteoblast function and ECM deposition, underscoring the need for further research into its long-term impact on bone homeostasis and human health induced by this emerging concern contaminant.

All living organisms on Earth have evolved mechanisms to counteract the effects of gravity. In space, however, shear forces, buoyancy-driven convection, and hydrostatic pressure are either eliminated or significantly reduced. Microgravity disrupts the balance between intracellular structures and external forces, leading to changes at both the cellular and subcellular levels. The absence of gravitational forces in microgravity significantly impacts cellular behavior, including changes in tumor cell morphology, cytoskeletal structure, and gene expression. Research has demonstrated that microgravity induces the three-dimensional aggregation of cancer cells into multicellular spheroids, which more closely resemble in vivo tumors. These spheroids exhibit altered behaviors, including increased apoptosis, autophagy, and reduced proliferation and migration. Such changes suggest that microgravity may offer a promising novel therapeutic approach for cancer treatment. However, the precise underlying mechanisms remain largely unexplored. This review examines current microgravity research platforms and explores how microgravity affects tumor cell molecular and biological behaviors, offering valuable insights into the potential for innovative cancer therapies.

Glioblastomas (GBM) is a highly malignant primary brain tumor with poor prognosis despite standard treatments of surgery, radiotherapy, and chemotherapy. Temozolomide (TMZ) is a key chemotherapeutic agent for GBM but is limited by resistance mechanisms. In this study, we developed a novel imidazotetrazine analogs to overcome TMZ resistance with enhanced therapeutic efficacy. CCK8 assays demonstrated that QX302 showed remarkable potency and effectively inhibited the viability of U251, U87, T98G, and HCT116 cells in a dose- and time-dependent manner. Proteomic analysis indicated that QX302 affected critical pathways, including nucleotide binding, chromatin organization, cell cycle regulation, and DNA repair processes. Further investigations revealed that QX302 effectively inhibits glioma spheroid growth and induces cell cycle arrest, ferroptosis, and apoptosis. Notably, QX302 induced DNA damage in cancer cells via the alkylation of DNA, leading to increased sensitivity to Olaparib via the base excision repair signaling pathway. Predictive modeling demonstrated QX302 has a favorable pharmacokinetic profile, including high blood-brain barrier permeability, highlighting its potential as a central nervous system-penetrating therapeutic agent. In conclusion, QX302 represents a promising therapeutic strategy for GBM, offering improved efficacy and the potential for use in combinatorial therapy with lower effective doses compared to TMZ.