Cell Death & Disease最新文献

The Triple-Negative Breast Cancer (TNBC) subtype constitutes 15-20% of breast cancer cases and is associated with the poorest clinical outcomes. Distant metastasis, particularly to the lungs, is a major contributor to the high mortality rates in breast cancer patients. Despite this, there has been a lack of comprehensive insights into the heterogeneity of metastatic tumors and their surrounding ecosystem in the lungs. In this study, we utilized spatial RNA sequencing technology to investigate the heterogeneity of lung metastatic tumors and their microenvironment in two spontaneous lung metastatic mouse models. Our findings revealed an increase in metabolic-related genes within the cancer cells, with the hub gene Dlat (Dihydrolipoamide S-Acetyltransferase) showing a significant association with the development of lung metastatic tumors. Upregulation of Dlat led to the reprogramming of fatty acid utilization, markedly enhancing the bioenergetic capacity of cancer cells. This finding was corroborated by the increased dependence on fatty acid utilization in lung metastatic cancer cells, and inhibition of Dlat in breast cancer cells exhibited a reduced oxygen consumption rate. Consequently, inhibition of Dlat resulted in decreased survival capacity of breast cancer by reducing cancer stem cell properties and cell adhesion in the lung in vivo. The three cell components within the lung metastatic niche, including CD163⁺ macrophages, neutrophils, and endothelial cells, expressed elevated levels of ApoE, leading to the secretion of various protumorigenic molecules that promote cancer cell growth in the lung. These molecules include galectin-1, S100A10, S100A4, and S100A6. Collectively, our findings highlight the lipid metabolism reprogramming of cancer and components of the tumor microenvironment that support lung metastasis of TNBC breast cancer.

Neuronal necroptosis appears to be suppressed by the deubiquitinating enzyme A20 and is capable to regulate the polarization of microglia/macrophages after cerebral ischemia. We have demonstrated that hypoxic preconditioning (HPC) can alleviate receptor interacting protein 3 (RIP3)-induced necroptosis in CA1 after transient global cerebral ischemia (tGCI). However, it is still unclear whether HPC serves to regulate the phenotypic polarization of microglia/macrophages after cerebral ischemia by mitigating neuronal necroptosis. We hence aim to elucidate the underlying mechanism(s) by which the ubiquitination of RIP3-dependent necroptosis regulated by A20 affects microglia/macrophages phenotype after cerebral ischemic tolerance. We found that microglia/macrophages in CA1 of rats underwent M1 and M2 phenotypic polarization in response to tGCI. Notably, the treatment with HPC, as well as inhibitors of necroptosis, including Nec-1 and mixed lineage kinase domain-like (MLKL) siRNA, attenuated neuroinflammation associated with M1 polarization of microglia/macrophages induced by tGCI. Mechanistically, HPC was revealed to upregulate A20 and in turn enhance the interaction between A20 and RIP3, thereby reducing K63-linked polyubiquitination of RIP3 in CA1 after tGCI. Consequently, RIP3-dependent necroptosis and the M1 polarization of microglia/macrophages were blocked either by HPC or via overexpression of A20 in neurons, which ultimately mitigated cerebral injury in CA1 after tGCI. These data support that A20 serves as a crucial mediator of microglia/macrophages polarization by suppressing neuronal necroptosis in a RIP3 ubiquitination-dependent manner after tGCI. Also, a novel mechanism by which HPC functions in cerebral ischemic tolerance is elucidated.

Fine particulate matter (PM2.5) exposure has been associated with increased incidence and mortality of lung cancer. However, the molecular mechanisms underlying PM2.5 carcinogenicity remain incompletely understood. Here, we identified that PM2.5 suppressed the expression of tRNA methyltransferase FTSJ1 and Am modification level of tRNA in vitro and in vivo. FTSJ1 downregulation enhanced glycolytic metabolism of non-small cell lung cancer (NSCLC) cells, as indicated by increased levels of lactate, pyruvate, and extracellular acidification rate (ECAR). Whereas treatment with glycolytic inhibitor 2-DG reversed this effect. In contrast, upregulation of FTSJ1 significantly suppressed glycolysis of NSCLC cells. Mechanistically, the silencing of FTSJ1 increased NSCLC cell proliferation and glycolysis through enhancing the expression and translation of PGK1. In human NSCLC tumor samples, FTSJ1 expression was negatively correlated with PGK1 expression level and the SUVmax value of PET/CT scan. In summary, our work reveals a previously unrecognized function of PM2.5-downregulated FTSJ1 on PGK1-mediated glycolysis in NSCLC, suggesting that targeted upregulation of FTSJ1 may represent a potential therapeutic strategy for NSCLC.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378^high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378^high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378^high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378^high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378^high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.

Effectively interfering with endoplasmic reticulum (ER) function in tumor cells and simultaneously activating an anti-tumor immune microenvironment to attack the tumor cells are promising strategies for cancer treatment. However, precise ER-stress induction is still a huge challenge. In this study, we synthesized a near-infrared (NIR) probe, NIR-715, which induces tumor cell death and inhibits tumor growth without causing apparent side effects. NIR-715 triggers severe ER stress and immunogenic cell death (ICD) after visible light exposure. NIR-715 induced ICD-associated HMGB1 release in vitro and anti-tumor immune responses, including increased cytotoxic T lymphocyte (GZMB⁺ CD8⁺ T cell) infiltration and decreased numbers of exhausted T lymphocytes (PD-L1⁺ CD8⁺ T cell). These findings suggest that NIR-715 may be a novel agent for "cold" tumor photodynamic therapy (PDT). Schematic illustration of NIR-715 photodynamic therapy for visible light-triggered, endoplasmic reticulum-targeting antitumor therapy.

Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung cancer patients' survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.

The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death globally. Also, there is still a lack of effective therapeutic strategies for CRC patients owing to a poor understanding of its pathogenesis. Here, we analysed differentially expressed genes in CRC and identified CPNE7 as a novel driver of colorectal tumorigenesis. CPNE7 is highly expressed in CRC and negatively correlated with patients' prognosis. Upregulation of CPNE7 promotes proliferation and metastasis of cancer cells in vitro and in vivo, and vice versa. Mechanistically, CPNE7 interacts with NONO to initiate ZFP42 transcription, thus promoting CRC progression. Moreover, ZFP42 knockdown inhibits tumor cell proliferation and migration while promoting apoptosis. Notably, delivery of CPNE7 shRNA or the small molecule gramicidin, which blocks the interaction between CPNE7 and NONO, hinders tumor growth in vivo. In conclusion, our findings demonstrate that the CPNE7-NONO-ZFP42 axis promotes colorectal tumorigenesis and may be a new potential therapeutic target.

Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.

Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.