Cell Death & Disease最新文献

The association of necrosis in tumors with poor prognosis implies a potential tumor-promoting role. However, the mechanisms underlying cell death in this context and how damaged tissue contributes to tumor progression remain unclear. Here, we identified p38 mitogen-activated protein kinases (p38 MAPK, a.k.a. p38) as a key player in promoting cell death and the inflammatory response to ischemic stress associated with necrotic tumors. We found that glioblastoma (GBM) cells expressing patient-derived Kirsten rat sarcoma (KRAS) or phosphoinositide-3-kinase (PI3K) active mutants showed enhanced cell death under ischemia-mimetic conditions in vitro and were more likely to develop into necrotic tumors in vivo. Cell death in both settings depended on p38, which is also required for tumor progression driven by KRAS or PI3K. Under ischemia-mimetic conditions, GBM cells undergo reactive oxygen species (ROS)-dependent cell death. Gene expression in these cells recapitulated multiple features observed in peri-necrotic tumors from patient GBM. Further studies showed the involvement of a positive feedback loop between the p38-MAPK-activated protein kinase 2 (MAPKAPK2, a.k.a. MK2) signaling axis and the unfolded protein response signaling components activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α) in driving ischemic tumor cell death. This signaling cascade was further potentiated by RAS or PI3K activation under ischemic conditions, contributing to the inflammatory gene expression response. Therefore, our study suggests that p38 could be targeted to relieve the inflammatory response in necrotic tumors and inhibit GBM progression.

Helicobacter pylori (H. pylori) infection is a well-established risk factor for gastric cancer, primarily due to its virulence factor, cytotoxin-associated gene A (CagA). Although PD-L1/PD-1-mediated immune evasion is critical in cancer development, the impact of CagA on PD-L1 regulation remains unclear. This study revealed that H. pylori CagA upregulated squalene epoxidase (SQLE) expression, a key enzyme in the cholesterol biosynthesis pathway. Elevated SQLE activity increased cellular palmitoyl-CoA levels, enhancing PD-L1 palmitoylation while decreasing its ubiquitination. This ultimately increases PD-L1 stability, suppressing T cell activity and facilitating immune evasion in gastric cancer. In summary, our findings highlight the crucial role of the CagA-SQLE-PD-L1 axis in gastric cancer progression, suggesting potential therapeutic strategies for targeting CagA-positive gastric cancer.

Neuroinflammation is a key factor in the pathogenesis of Parkinson's disease (PD). Activated microglia in the central nervous system (CNS) and infiltration of peripheral immune cells contribute to dopaminergic neuron loss. However, the role of peripheral immune responses, particularly triggering receptor expressed on myeloid cells-1 (TREM-1), in PD remains unclear. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD mouse model, we examined TREM-1 expression and monocyte infiltration in the substantia nigra pars compacta (SNpc). We found that MPTP increased peripheral monocytes, and deletion of peripheral monocytes protected against MPTP neurotoxicity in the SNpc. TREM-1 inhibition, both genetically and pharmacologically, reduced monocyte infiltration, alleviated neuroinflammation, and preserved dopaminergic neurons, resulting in improved motor function. Furthermore, adoptive transfer of TREM-1-expressing monocytes from PD model mice to naive mice induced neuronal damage and motor deficits. These results underscore the critical role of peripheral monocytes and TREM-1 in PD progression, suggesting that targeting TREM-1 could be a promising therapeutic approach to prevent dopaminergic neurodegeneration and motor dysfunction in PD. Schematic diagram of monocyte TREM-1-mediated dopaminergic neuron damage. The figure illustrates that in experimental MPTP-induced PD model mice, the number of inflammatory monocytes in the peripheral blood increases, after which the monocytes infiltrate the CNS through the Blood-Brain Barrier(BBB). These infiltrating monocytes increase the release of inflammatory cytokines and eventually cause neuronal injury. TREM-1 gene deletion and pharmacological blockade limit inflammatory monocyte recruitment into the SNpc and ameliorate neuroinflammatory events and the loss of dopaminergic neurons.

Sterile alpha and Toll/interleukin-1 receptor motif containing 1 (SARM1), a nicotinamide adenine dinucleotide (NAD)-utilizing enzyme, mediates axon degeneration (AxD) in various neurodegenerative diseases. It is activated by nicotinamide mononucleotide (NMN) to produce a calcium messenger, cyclic ADP-ribose (cADPR). This activity is blocked by elevated NAD level. Here, we verified this metabolic regulation in somatic HEK-293T cells by overexpressing NMN-adenyltransferase to elevate cellular NAD, which resulted not only in inhibition of their own SARM1 from producing cADPR but, surprisingly, also in the 5-10 neighboring wildtype cells in mixed cultures via connexin (Cx)-43. Direct visualization of gap junction intercellular communication (GJIC) was achieved by incubating cells with a permeant probe, PC11, which is converted by SARM1 into PAD11, a fluorescent NAD analog capable of traversing GJs. Extending the findings to dorsal root ganglion neurons, we further showed that CZ-48, a permeant NMN analog, or axotomy, activated SARM1 and the produced PAD11 was transferred to contacting axons via GJIC. The gap junction involved was identified as Cx36 instead. This neuronal GJIC was demonstrated to be functional, enabling healthy neurons to protect adjacent axotomized axons from degeneration. Inhibition of GJIC in mice by AAV-PHP.eB-mediated knockdown of Cx36 in brain induced neuroinflammation, which in turn activated SARM1 and resulted in axon degeneration as well as behavioral deficits. Our results demonstrate a novel intercellular regulation mechanism of SARM1 and reveal a protective role of healthy tissue against AxD induced by injury or neuroinflammation.

Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m⁶A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m⁶A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m⁶A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m⁶A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m⁶A/YTHDF2/SOCS2 pathway, both of which require the m⁶A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.

This research demonstrates that DCC-2036 (Rebastinib), a potent third-generation tyrosine kinase inhibitor (TKI), effectively suppresses tumor growth in colorectal cancer (CRC) models with functional immune systems. The findings underscore the capacity of DCC-2036 to enhance both the activation and cytotoxic functionality of CD8⁺ T cells, which are crucial for facilitating anti-tumor immune responses. Through comprehensive multi-omics investigations, significant shifts in both gene and protein expression profiles were detected, notably a marked decrease in DKK1 levels. This reduction in DKK1 was linked to diminished CD8⁺ T cell effectiveness, correlating with decreased FGR expression. Moreover, our findings identify FGR as a pivotal modulator that influences DKK1 expression via the PI3K-AKT-SP1 signaling cascade. Correlative analysis of clinical specimens supports the experimental data, showing that increased levels of FGR and DKK1 in CRC tissues are associated with inferior clinical outcomes and reduced efficacy of immunotherapeutic interventions. Consequently, targeting the FGR-AKT-SP1-DKK1 pathway with DCC-2036 could potentiate immunotherapy by enhancing CD8⁺ T cell functionality and their tumor infiltration. This strategy may contribute significantly to the refinement of therapeutic approaches for CRC, potentially improving patient prognoses.

Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether polyploidy is an adverse, benign or even favourable outcome. We show Aurora B kinase inhibitors efficiently promote polyploidy in many cell types, resulting in the cell cycle exit in RB and p53 functional cells, but hyper-polyploidy in cells with loss of RB and p53 function. These hyper-polyploid cells (>8n DNA content) are viable but have lost long-term proliferative potential in vitro and fail to form tumours in vivo. Investigation of mitosis in these cells revealed high numbers of centrosomes that were capable of supporting functional mitotic spindle poles, but these failed to progress to anaphase/telophase structures even when AURKB inhibitor was removed after 2-3 days. However, when AURKB inhibitor was removed after 1 day and cells had failed a single cytokinesis to become tetraploid, they retained colony forming ability and long-term proliferative potential. Mathematical modelling of the potential for polyploid cells to produce viable daughter cells demonstrated that cells with >8n DNA and >4 functional spindle poles approach zero probability of a viable daughter, supporting our experimental observations. These findings demonstrate that tetraploidy is tolerated by tumour cells, but higher ploidy states are incompatible with long-term proliferative potential. Model for AURKBi driven hyper-polyploid cells formation and fate. Aurora B inhibitor (AURKBi) treatment of RB+p53 defective cells efficiently promotes failed cell division. One failed cell division produces three possible outcomes, continued proliferation of the tetraploid daughter, cell death, or if AURKBi is continued, high polyploid states. Once cell have failed cell division >twice and have >8n DNA content they will continue to undergo rounds of endomitosis even in the absence of AURKBi to either become viable hyper-polyploid or die. The hyper-polyploid cells have no long-term proliferative potential.

Ubiquitin-specific protease 25 (USP25), a member of the deubiquitination family, plays an important role in protein ubiquitination, degradation, inflammation, and immune regulation. However, the role and mechanism of USP25 in ulcerative colitis (UC) remain unclear. To study the role and mechanism of USP25 in UC, bioinformatics analysis and research are conducted on clinical patients with UC, Usp25 knockout (Usp25^-/-) mice, intestinal epithelial cell-specific knockout signal transducer and activator of transcription 3 (Stat3) (Villin-Cre Stat3^fl/fl) mice, and human colonic epithelial cells. Results show that the expression of USP25 is decreased in patients with UC and mice with dextran sulfate sodium salt (DSS)-induced colitis and that USP25 deficiency exacerbates UC by destroying the intestinal mucosal barrier, however, overexpression of USP25 can alleviate colitis. Mechanistically, USP25 reduces the degradation of phosphor-STAT3^Y705 at lysine 409 by catalyzing K48-linked deubiquitination. Further, this study demonstrates the aggravation of DSS-induced colitis by intestinal epithelial cell-specific knockout Stat3 in mice, while Stat3 overexpression by adeno-associated virus attenuates colitis in DSS-induced Usp25^-/- mice. Together, these results showed that USP25 ameliorates UC by regulating the degradation of phosphor-STAT3. Collectively, USP25 is a specific STAT3 regulator that can be targeted in UC.