Cell Death & Disease最新文献

Dysregulation of SMAD4 (i.e. somatic mutation) is strongly associated with poor pancreatic ductal adenocarcinoma (PDAC) prognosis, yet the molecular mechanisms remain underlying this relationship obscure. Previously, we discovered that SMAD4 mutation renders pancreatic cancer resistant to radiotherapy via promotion of autophagy. In the current work, we observed a downregulation of the protein level of SMAD4 in PDAC as compared with adjacent normal tissue, and that such SMAD4^low PDAC failed to benefit from chemotherapy. Furthermore, we observed that SMAD4 depletion dramatically enhanced DNA repair capacity in response to irradiation (IR) or a radiomimetic chemical. Interestingly, we found the radiomimetic chemical having induced a robust translocation of SMAD4 into the nucleus, where a direct interaction was shown to occur between the MH1 domain of SMAD4 and the DBD domain of PARP1. Functionally, the SMAD4-PARP1 interaction was found to perturb the recruitment of PARP1 to DNA damage sites. Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.

The mitochondrial malic enzyme 2 (ME2), which is frequently elevated during carcinogenesis and may be a target for cancer therapy, catalyzes the conversion of malate to pyruvate. The processes controlling ME2 activity, however, remain largely unclear. In this work, we show that human hepatocellular carcinoma (HCC) tissues contain high levels of ME2 and that the methylation of ME2 stimulates the growth and migration of HCC cells. Furthermore, we observed that ME2 interacts with protein arginine methyltransferase 1 (PRMT1) and that ME2 enzymatic activity is activated by mutation of ME2 at lysine 67. Mitochondrial respiration was markedly increased by activated ME2, which promoted cell division and carcinogenesis. Furthermore, a negative prognosis for patients was strongly linked with the expression levels of PRMT1 and ME2 R67K in HCC tissues. These findings imply that hepatocellular carcinoma growth is aided by PRMT1-mediated ME2 methylation, that is an essential signaling event that cancer cells need to continue mitochondrial respiration.

Embryonal carcinoma (EC), characterized by a high degree of stemness similar to that of embryonic stem cells, is the most malignant subtype within non-seminomatous testicular germ cell tumors (TGCTs). However, the mechanisms underlying its malignancy remain unknown. In this study, we employed single-cell RNA sequencing to analyze four non-seminoma samples. Our differential expression analysis revealed high expression of SERPINB9 in metastatic EC cells. We conducted in vitro experiments to further investigate SERPINB9's role in the progression of EC. Functionally, the knockdown of SERPINB9 in NCCIT and NTERA-2 leads to a diminished migratory capability and decreased cis-platin resistance, as demonstrated by Transwell migration assay and drug sensitivity assay. Moreover, embryoid bodies showed reduced size and lower OCT4 expression, alongside heightened expression of differentiation markers AFP, ACTA2, and CD57 in shSERPINB9 cells. In vivo, the role of SERPINB9 in maintaining cancer stemness was validated by the limiting dilution assay. Mechanistically, Bulk RNA-seq further showed downregulation of ERK1/2 signaling and WNT signaling pathways with concomitant upregulation of differentiation pathways subsequent to SERPINB9 knockdown. Additionally, the analysis indicated increased levels of cytokines linked to tertiary lymphoid structures (TLS), such as IL6, IL11, IL15, CCL2, CCL5, and CXCL13 in shSERPINB9 cells, which were further validated by ELISA. Our research indicates that SERPINB9 plays a key role in driving tumor progression by enhancing tumor stemness and suppressing TLS. This study stands as the first to elucidate the molecular signature of non-seminomas at a single-cell level, presenting a wealth of promising targets with substantial potential for informing the development of future therapeutic interventions.

Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. Hence, the demand for preclinical research into atherosclerotic inflammation is on the horizon. Indeed, the acquisition of an in-depth knowledge of the molecular and cellular mechanisms of inflammation in atherosclerosis should allow us to identify novel therapeutic targets with translational merits. In this review, we aimed to critically discuss and speculate on the recently identified molecular and cellular mechanisms of inflammation in atherosclerosis. Moreover, we delineated various signaling cascades and proinflammatory responses in macrophages and other leukocytes that promote plaque inflammation and atherosclerosis. In the end, we highlighted potential therapeutic targets, the pros and cons of current interventions, as well as anti-inflammatory and atheroprotective mechanisms.

G-quadruplex (G4) is a noncanonical DNA secondary structure known to induce DNA damage and regulate the expression of immune-related genes. We aim to exploit the G4 folding as a treatment strategy to trigger anti-tumor immune response. In this study, we observe that the abundant genomic G4 in epithelial cells coexists with increased infiltration of CD8⁺ T cells in colorectal cancer tissue. Furthermore, our data substantiate the inhibitory effect of the G4 ligand TMPyP4 on cancer progression while concurrently stimulating anti-tumor immunity. Mechanistically, TMPyP4 impedes cancer cell proliferation and induces G2/M cell cycle arrest. Additionally, in vivo experiments demonstrate that TMPyP4 enhances the anti-tumor immune response by triggering DNA damage and activating the cGAS-STING pathway, which fosters CD8⁺ T cell activation and dendritic cell maturation. Importantly, the combined treatment of TMPyP4 and anti-PD1 exhibits a synergistic therapeutic effect on colorectal cancer. In summary, our findings underscore the potential of the G4 ligand TMPyP4 as a dual strategy to target colorectal cancer: inhibiting cancer progression and augmenting anti-tumor immunity through the activation of cGAS-STING pathway.

The therapeutic options for Alzheimer's disease (AD) are limited, underscoring the critical need for finding an effective regulator of Aβ42 production. In this study, with 489 human postmortem brains, we revealed that homotrimer G protein subunit gamma 5 (GNG5) expression is upregulated in the hippocampal-entorhinal region of pathological AD compared with normal controls, and is positively correlated with Aβ pathology. In vivo and in vitro experiments confirm that increased GNG5 significantly promotes Aβ pathology and Aβ42 production. Mechanically, GNG5 regulates the cleavage preference of γ-secretase towards Aβ42 by directly interacting with the γ-secretase catalytic subunit presenilin 1 (PS1). Moreover, excessive GNG5 increases the protein levels and the activation of Rab5, leading to the increased number of early endosomes, the major cellular organelle for production of Aβ42. Furthermore, immunoprecipitation and immunofluorescence revealed co-interaction of Aβ42 with GPCR family CXCR2, which is known as the receptor for IL-8, thus facilitating the dissociation of G-proteins βγ from α subunits. Treatment of Aβ42 in neurons combined with structure prediction indicated Aβ42 oligomers as a new ligand of CXCR2, upregulating γ subunit GNG5 protein levels. The co-localizations of GNG5 and PS1, CXCR2 and Aβ42 were verified in eight human brain regions. Besides, GNG5 is significantly reduced in extracellular vesicles (EVs) derived from cerebral cortex or serum of AD patients compared with healthy cognition controls. In brief, GNG5 is a novel regulator of Aβ42 production, suggesting its clinical potential as a diagnosis biomarker and the therapeutic target for AD. The GNG5 content in EVs derived from serum and brain tissue of patients with AD significantly reduced. The GNG5 expression in the hippocampal-entorhinal neurons of donors with pathological AD significantly increased, and can exist in homotrimer subtypes. GNG5 expression positively correlates with Aβ pathology and Aβ42 production. Homotrimer-GNG5 binds to the γ-secretase catalytic subunit PS1 and preferentially generates Aβ42 in early endosome. GNG5 leads to enhanced Rab5 protein and activation levels, increased number of early endosome, promoting Aβ42 production. Further, Aβ42 binds to CXCR2 to upregulate GNG5 levels in a feedback loop.

This study aims to explore the inhibitory effects of combined metformin and simvastatin therapy on the malignant progression of glioma. The research specifically examines how the maturation of SREBP2 as a transcription factor affects the expression of GLUT1 and GLUT6 in glioma cells. Additionally, it investigates the impact of this combination therapy on the biological functions and energy metabolism of glioma cells. To assess the functions of GLUT1/6, sh-GLUT1/6 plasmids were employed. The study determined the half-maximal inhibitory concentrations (IC50) of metformin and simvastatin using the CCK-8 assay. Subsequently, the effects of these drugs on glioma metabolism, proliferation, and apoptosis were explored in vitro and in vivo, using drug concentrations significantly lower than their respective IC50 values. The impact of drug treatment on GLUT1/6 and SREBP2 expression levels was also evaluated. The study elucidated the significant impact of GLUT1/6 on glioma cell functions, resulting in decreased glucose uptake. Moreover, it unveiled the regulatory role of SREBP2 in GLUT1 and GLUT6 transcription, alongside revealing differential expression of SREBP2 precursor and mature forms within gliomas. Following combined drug therapy, GLUT1/6 expression decreased, while the precursor form of SREBP2 increased, and mature SREBP2 reduced. This dual-drug treatment effectively modulated glioma cell energy metabolism. Subsequent in vivo experiments affirmed the augmented anti-tumor efficacy of combined drug therapy. Specifically, the synergistic action of metformin and simvastatin reshaped glioma metabolism, curbed malignant proliferation, promoted apoptosis, and demonstrated superior anti-tumor effects both in vitro and in vivo compared to individual administration of metformin or simvastatin. Importantly, the combination therapy achieved these effects at lower doses, rendering it a safer treatment option.

Biallelic mutations in PIGK cause GPI biosynthesis defect 22 (GPIBD22), characterized with developmental delay, hypotonia, and cerebellar atrophy. The understanding of the underlying causes is limited due to the lack of suitable disease models. To address this gap, we generated a mouse model with PIGK deficits, specifically in Purkinje cells (Pcp2-cko) and an induced pluripotent stem cell (iPSC) model using the c.87dupT mutant (KI) found in GPIBD22 patients. Pcp2-cko mice demonstrated cerebellar atrophy, ataxia and progressive Purkinje cells loss which were accompanied by increased apoptosis and neuroinflammation. Similarly, KI iPSCs exhibited increased apoptosis and accelerated neural rosette formation, indicating that PIGK defects could impact early neural differentiation that confirmed by the RNA-Seq results of neural progenitor cells (NPCs). The increased apoptosis and accelerated NPC differentiation in KI iPSCs are associated with excessive unfolded protein response (UPR) pathway activation, and can be rescued by UPR pathway inhibitor. Our study reveals potential pathogenic mechanism of GPIBD22 and providing new insights into the therapeutic strategy for GPIBD.

Ferroptosis, a regulated form of cell death dependent on reactive oxygen species (ROS), is characterized by iron accumulation and lethal lipid peroxidation. Mitochondria serve as the primary source of ROS and thus play a crucial role in ferroptosis initiation and execution. This study highlights the role of mitochondrial ROS and the significance of voltage-dependent anion channel 1 (VDAC1) oligomerization in ferroptosis induced by cysteine deprivation or ferroptosis-inducer RSL3. Our results demonstrate that the mitochondria-targeted antioxidants MitoQ and MitoT effectively block ferroptosis induction and that dysfunction of complex III of the mitochondrial electron transport chain contributes to ferroptosis induction. Pharmacological inhibitors that target VDAC1 oligomerization have emerged as potent suppressors of ferroptosis that reduce mitochondrial ROS production. These findings underscore the critical involvement of mitochondrial ROS production via complex III of the electron transport chain and the essential role of VDAC1 oligomerization in ferroptosis induced by cysteine deprivation or RSL3. This study deepens our understanding of the intricate molecular networks governing ferroptosis and provides insights into the development of novel therapeutic strategies targeting dysregulated cell death pathways.

Aurora B kinase (AURKB) inhibitors have been trialled in a range of different tumour types but are not approved for any indication. Expression of the human papilloma virus (HPV) oncogenes and loss of retinoblastoma (RB) protein function has been reported to increase sensitivity to AURKB inhibitors but the mechanism of their contribution to sensitivity is poorly understood. Two commonly reported outcomes of AURKB inhibition are polyploidy and senescence, although their relationship is unclear. Here we have investigated the major cellular targets of the HPV E6 and E7, p53 and RB, to determine their contribution to AURKB inhibitor induced polyploidy and senescence. We demonstrate that polyploidy is a universal feature of AURKB inhibitor treatment in all cell types including normal primary cells, but the subsequent outcomes are controlled by RB and p53. We demonstrate that p53 by regulating p21 expression is required for an initial cell cycle arrest by inhibiting both CDK2 and CDK4 activity, but this arrest is only triggered after cells have undergone two failed mitosis and cytokinesis. However, cells can enter senescence in the absence of p53. RB is essential for AURKB inhibitor-induced senescence. AURKB inhibitor induces rapid hypophosphorylation of RB independent of inhibition of CDK2 or CDK4 kinases and p53. This work demonstrates that p53 activation determines the timing of senescence onset, but RB is indispensable for senescence.