Cell Death & Disease最新文献

Research on the aetiology of neural tube defects (NTDs) has made progress in recent years. However, the molecular mechanism of apolipoproteins underlying NTDs development remains unclear. This study aimed to investigate the function of apolipoprotein M (ApoM) in the pathogenesis of NTDs and its underlying mechanisms. We demonstrated that ApoM expression was reduced in the spinal cord samples of rat models and human fetuses with NTDs respectively. Specifically, lack of ApoM resulted in reduced cytosolic localization of Elavl2 and caused Nnt mRNA degradation, which further led to impaired cell homeostasis by suppressing PINK1-PRKN-mediated mitophagy and promoting apoptosis and subsequent NTDs formation. Moreover, Zic3 directly interacted with the promoter of ApoM and activated its transcription. Lastly, intra-amniotic delivery of adenoviral recombinant Zic3 or ApoM could promote mitophagy and alleviate apoptosis in spinal cords of NTDs. Collectively, these findings highlight the important role of the Zic3-ApoM-Elavl2-Nnt axis in cellular homeostasis during neural tube development, thereby revealing an intracellular molecular regulatory mechanism of ApoM, providing a mechanistic basis for understanding embryonic neural development, and offering experimental evidence for potential therapeutic targets for NTDs.

As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.

Cancer-associated fibroblasts (CAFs) play important roles in the occurrence and development of hepatocellular carcinoma (HCC) and are a key component of the immunosuppressive microenvironment. However, the origin of CAFs has not been fully elucidated. We employed single-cell sequencing technology to identify the dynamic changes in different subsets of fibroblasts at different time points in rat primary HCC model. Inflammation-associated CAFs (Pdgfrα⁺ CAFs) were subsequently identified, which demonstrated a significant correlation with the survival duration of HCC patients and a dual role in the tumour microenvironment (TME). On the one hand, they secrete the chemokines CCL3 and CXCL12, which recruit macrophages to the tumour site. On the other hand, they produce TGFβ, inducing the polarization of these macrophages towards an immunosuppressive phenotype. According to the in vitro and in vivo results, hepatic progenitor cells (HPCs) can aberrantly differentiate into PDGFRα⁺ CAFs upon stimulation with inflammatory cytokine. This differentiation is mediated by the activation of the MAPK signaling pathway and the downstream transcription factor ERG via the TLR4 receptor. Downregulating the expression of ERG in HPCs significantly reduces the number of PDGFRα⁺ CAFs and the infiltration of tumour-associated macrophages in HCC, thereby suppressing hepatocarcinogenesis. Collectively, our findings elucidate the distinct biological functions of PDGFRα⁺ cancer-associated fibroblasts (PDGFRα⁺ CAFs) within the TME. These insights contribute to our understanding of the mechanisms underlying the establishment of an immunosuppressive microenvironment in HCC, paving the way for the exploration of novel immunotherapeutic strategies tailored for HCC treatment.

Neurite degeneration (ND) precedes cell death in many neurodegenerative diseases. However, it remains unclear how this compartmentalized cell death process is orchestrated in the central nervous system (CNS). The establishment of a CNS axotomy model (using modified 3D LUHMES cultures) allowed us to study metabolic control of ND in human midbrain-derived neurons without the use of toxicants or other direct disturbance of cellular metabolism. Axotomy lead to a loss of the NAD⁺ synthesis enzyme NMNAT2 within 2 h and a depletion of NAD⁺ within 4-6 h. This process appeared specific, as isolated neurites maintained ATP levels and a coupled mitochondrial respiration for at least 6 h. In the peripheral nervous system (PNS) many studies observed that NAD⁺ metabolism, in particular by the NADase SARM1, plays a major role in the ND occurring after axotomy. Since neither ferroptosis nor necroptosis, nor caspase-dependent apoptosis seemed to be involved in neurite loss, we investigated SARM1 as potential executioner (or controller). Knock-down or expression of a dominant-negative isoform of SARM1 indeed drastically delayed ND. Various modifications of NAD⁺ metabolism known to modulate SARM1 activity showed the corresponding effects on ND. Moreover, supplementation with NAD⁺ attenuated ND. As a third approach to investigate the role of altered NAD⁺ metabolism, we made use of the WLD(s) protein, which has been found in a mutant mouse to inhibit Wallerian degeneration of axons. This protein, which has a stable NMNAT activity, and thus can buffer the loss of NMNAT2, protected the neurites by stabilizing neurite NAD⁺ levels. Thus CNS-type ND was tightly linked to neurite metabolism in multiple experimental setups. Based on this knowledge, several new strategies for treating neurodegenerative diseases can be envisaged.

Approximately 80% of nasopharyngeal carcinoma (NPC) patients exhibit EGFR overexpression. The overexpression of EGFR has been linked to its potential role in modulating major histocompatibility complex class I (MHC-I) molecules. We discovered that EGFR, operating in a kinase-independent manner, played a role in stabilizing the expression of SLC7A11, which subsequently inhibited MHC-I antigen presentation. This mechanism, in turn, provided protection to NPC cells against T cell-mediated cytotoxicity. The underlying molecular processes revealed that the high and stable expression of SLC7A11 hindered the nuclear entry of GR, thereby suppressing TAP1 transcription and the presentation of MHC-I molecules. Additionally, elevated SLC7A11 expression led to an increase in FAF2 expression and triggered ERAD-dependent degradation of MHC-I, resulting in a reduction of MHC-I molecules on the cell membrane. The NPC patients exhibiting high EGFR and low MHC-I expression, combined with a scarcity of CD8⁺ T cells (EGFR^highMHC-I^lowCD8^few phenotype), experienced considerably shorter overall survival times compared to other situations. What is more, our study demonstrated that sorafenib had the capability to enhance the MHC-I antigen presentation process, thereby facilitating T cell-mediated killing of NPC cells via targeting SLC7A11. Consequently, targeting SLC7A11 with sorafenib emerges as a promising therapeutic strategy for the treatment of NPC.

Estrogen-related receptor α (ERRα) is dysregulated in many types of cancer and exhibits oncogenic activity by promoting tumorigenesis and metastasis of cancer cells. However, its defined role in renal cell carcinoma (RCC) has not been fully elucidated. To reveal the biological function of ERRα and determine the underlying regulatory mechanism in RCC, the quantitative proteomics analysis and mechanism investigation were conducted. The results demonstrated that ERRα promoted the proliferation and tumorigenesis of RCC cells by maintaining lysosome-dependent autophagy flux. ERRα inhibition impaired the transcriptional expression of LAMP2 and VAMP8 and blocked the fusion of autophagosomes with lysosomes, causing the impairment of the autophagy-lysosome pathway and tumor repression in RCC. Moreover, VHL mutant-induced hyperactive hypoxia signaling in RCC triggered p300/CBP-mediated acetylation at the DNA-binding domain of ERRα, and this acetylation promoted its affinity toward targeting DNA and Parkin-mediated ubiquitination and proteasome-dependent degradation. This regulatory model enhanced ERRα transactivation on the expression of LAMP2 and VAMP8, which then maintained autophagy flux and RCC progression. Pharmaceutical inhibition on ERRα acetylation-mediated autophagy-lysosome pathway led to growth repression and sunitinib sensitivity of RCC cells. Taken together, this study uncovered a novel regulatory mechanism of acetylation contributing to the transcriptional performance and the oncogenic role of ERRα in RCC progression by modulating the autophagy-lysosome pathway. These findings might provide a novel approach for the clinical diagnosis and resolution of sunitinib resistance of RCC.

Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128^-/- mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.

Small extracellular vesicles (sEVs), carrying PD-L1, have been implicated in immune evasion and tumor progression. However, understanding how PD-L1 sEVs are secreted still needs to be improved. We found that the secretion dynamics of PD-L1 sEVs is similar to that of other sEVs. Intracellular calcium and the associated downstream PKC signaling plays pivotal roles in releasing PD-L1 sEVs in non-small cell lung cancer cells (NSCLC). Particularly, we observed that knocking down PKCα has profound impacts on PD-L1 sEVs secretion, especially in the resting state and in the activated state, when induced by an intracellular calcium rise. Furthermore, our study revealed that PKCα regulates PD-L1 expression and PD-L1 sEVs secretion by influencing STAT1 phosphorylation and nuclear translocation in a p53-dependent manner. Notably, p53 can regulate STAT1 phosphorylation and nuclear localization, but it does not affect PKCα expression. This suggests that PKCα plays a significant role in regulating PD-L1 expression. Our findings suggest that targeting PKCα to modulate PD-L1 dynamics in NSCLC may be a promising therapeutic strategy to enhance the efficacy of immunotherapeutic interventions.

Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects.

The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3^R97H mutation, which not only fails to activate p53 but also impedes NR2E3^WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.