Cell Death Discovery最新文献

Cell cycle checkpoints, activated by stressful events, halt the cell cycle progression, and prevent the transmission of damaged DNA. These checkpoints prompt cell repair but also trigger cell death if damage persists. Decision-making between these responses is multifactorial and context-dependent, with the tumor suppressor p53 playing a central role. In many tumor cells, p53 alterations lead to G1/S checkpoint loss and the weakening of the G2 checkpoint, rendering cell viability dependent on the strength of the latter through mechanisms not fully characterized. Cells with a strong pro-survival drive can evade cell death despite substantial DNA lesions. Deciphering the integration of survival pathways with p53-dependent and -independent mechanisms governing the G2/M transition is crucial for understanding G2 arrest functionality and predicting tumor cell response to chemotherapy. The serine/threonine kinase GRK2 emerges as a signaling node in cell cycle modulation. In cycling cells, but not in G2 checkpoint-arrested cells, GRK2 protein levels decline during G2/M transition through a process triggered by CDK2-dependent phosphorylation of GRK2 at the S670 residue and Mdm2 ubiquitination. We report now that this downmodulation in G2 prevents the unscheduled activation of the PI3K/AKT pathway, allowing cells to progress into mitosis. Conversely, higher GRK2 levels lead to tyrosine phosphorylation by the kinase c-Abl, promoting the direct association of GRK2 with the p85 regulatory subunit of PI3K and AKT activation in a GRK2 catalytic-independent manner. Hyperactivation of AKT is conditioned by p53's scaffolding function, triggering FOXO3a phosphorylation, impaired Cyclin B1 accumulation, and CDK1 activation, causing a G2/M transition delay. Upon G2 checkpoint activation, GRK2 potentiates early arrest independently of p53 through AKT activation. However, its ability to overcome the G2 checkpoint in viable conditions depends on p53. Our results suggest that integrating the GRK2/PI3K/AKT axis with non-canonical functions of p53 might confer a survival advantage to tumor cells.

Age-related hearing loss (ARHL) is one of the most prevalent types of sensory decline in a superaging society. Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of ARHL, there are no effective preventive approaches for ARHL. Recent studies have suggested that oxidative stress-induced DNA damage responses (oxidative DDRs) drive cochlear cell senescence and contribute to accelerated ARHL, and autophagy could function as a defense mechanism against cellular senescence in auditory cells. However, the underlying mechanism remains unclear. Sodium arsenite (NaAsO₂) is a unique oxidative stress inducer associated with reactive oxygen species (ROS) that causes high-tone hearing loss similar to ARHL. Transcription factor EB (TFEB) functions as a master regulator of the autophagy‒lysosome pathway (ALP), which is a potential target during aging and the pathogenesis of various age-related diseases. Here, we focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO₂-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO₂ leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality. Then, intracellular ROS derived from damaged mitochondria play a role as a second messenger to induce premature senescence in auditory cells. These findings suggest that TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL. We have revealed the potential function of TFEB as a master regulator of the induction of oxidative stress-induced premature senescence and the senescence-associated secretion phenotype (SASP) in auditory cells, which regulates ALP and controls mitochondrial quality through ROS production.

The Bcl2-associated athanogene-3 (BAG3) protein, a critical regulator of cellular survival, has been identified as a potential therapeutic target in various malignancies. This study investigates the role of BAG3 within stromal fibroblasts and its interaction with B-cell chronic lymphocytic leukemia (B-CLL) cells. Previous research demonstrated that BAG3 maintains the active state of pancreatic stellate cells (PSCs) and aids pancreatic ductal adenocarcinoma (PDAC) spread via cytokine release. To explore BAG3's role in bone marrow-derived stromal fibroblasts, BAG3 was silenced in HS-5 cells using siRNA. In co-culture experiments with PBMCs from B-CLL patients, BAG3 silencing in HS-5 cells increased apoptosis and decreased phosphorylation of BTK, AKT, and ERK in B-CLL cells, thus disrupting their pro-survival key signaling pathways. The observation of fibroblast-activated protein (FAP) positive cells in infiltrated bone marrow specimens co-expressing BAG3 further support the involvement of the protein in fibroblast-mediated tumor survival. Additionally, BAG3 appears to support B-CLL survival by modulating cytokine networks, including IL-10 and CXCL12, which are essential for leukemic cell survival and proliferation. A robust correlation between BAG3 expression and the levels of CXCL12 and IL-10 was observed in both co-cultures and patient specimens. These findings point out the need for a more in-depth comprehension of the intricate network of interactions within the tumor microenvironment and provide valuable insights for the selection of new potential therapeutic targets in the medical treatment of CLL.

Stress granules (SGs) are considered to be the nonmembrane discrete assemblies present in the cytoplasm to cope with various environmental stress. SGs can promote the progression and drug resistance of hepatocellular carcinoma (HCC). Therefore, it is important to explore the mechanism of SG formation to reduce drug resistance in HCC. In this study, we demonstrate that p110α is required for SGs assembly. Mechanistically, the Arg-Gly (RG) motif of p110α is required for SG competence and regulates the recruitment of SG components. The methylation of p110α mediated by protein arginine methyltransferase 1 (PRMT1) interferes with the recruitment of p110α to SG components, thereby inhibiting the promotion of p110α to SGs. On this basis, we generated metal-polyphenol-network-coated R612F nanoparticles (MPN-R612F), which can efficiently enter HCC cells and maintain the hypermethylation state of p110α, thereby inhibiting the assembly of SGs and ultimately reducing the resistance of HCC cells to sorafenib. The combination of MPN-R612F nanoparticles and sorafenib can kill HCC cells more effectively and play a stronger anti-tumor effect. This study provides a new perspective for targeting SGs in the treatment of HCC.

The global incidence of thyroid cancer has increased over recent decades. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer and accounts for nearly 90% of all cases. Typically, PTC has a good prognosis. However, some PTC variants exhibit more aggressive behaviour, which significantly increases the risk of postoperative recurrence. Over the past decade, the high metastatic potential of PTC has drawn the attention of many researchers and these studies have provided useful molecular markers for improved diagnosis, risk stratification and clinical approaches. The aim of this review is to discuss the progress in epidemiology, metastatic features, risk factors and molecular mechanisms associated with PTC aggressiveness. We present a detailed picture showing that epithelial-to-mesenchymal transition, cancer metabolic reprogramming, alterations in important signalling pathways, epigenetic aberrations and the tumour microenvironment are crucial drivers of PTC metastasis. Further research is needed to more fully elucidate the pathogenesis and biological behaviour underlying the aggressiveness of PTC.

Telomerase reverse transcriptase (Tert) has been found to have a protective effect on telomeric DNA, but whether it could improve the repair of reactive oxygen species (ROS)-induced DNA damage and promote myocardial regenerative repair after myocardial infarction (MI) by protecting telomeric DNA is unclear. The immunofluorescence staining with TEL-CY3 and the TeloTAGGG Telomerase PCR ELISA kit were used to show the telomere length and telomerase activity. The heart-specific Tert-deletion homozygotes were generated by using commercial Cre tool mice and flox heterozygous mice for mating. We measured the telomere length and telomerase activity of mouse cardiomyocytes (CMs) at different days of age, and the results showed that they were negatively correlated with age. Overexpressed Tert could enhance telomerase activity and lengthen telomeres, thereby repairing the DNA damage induced by ROS and promoting CM proliferation in vitro. The in vivo results indicated that enhanced Tert could significantly improve cardiac function and prognosis by alleviating CM DNA damage and promoting angiogenesis post-MI. In terms of mechanism, DNA pulldown assay was used to identify that nuclear ribonucleoprotein A2B1 (hnRNPA2B1) could be an upstream regulator of Tert in CMs. Overexpressed Tert could activate the NF-κB signaling pathway in CMs and bind to the VEGF promoter in the endothelium to increase the VEGF level. Further immunoblotting showed that Tert protected DNA from ROS-induced damage by inhibiting ATM phosphorylation and blocking the Chk1/p53/p21 pathway activation. HnRNPA2B1-activated Tert could repair the ROS-induced telomeric DNA damage to induce the cell cycle re-entry in CMs and enhance the interaction between CMs and endothelium, thus achieving cardiac regenerative repair after MI.

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions.

CAFs (cancer-associated fibroblasts) are highly flexible cells of the cancer microenvironment. They produce the extracellular matrix (ECM) constituents that form the structure of the tumor stroma but are also a source of metabolites, growth factors, chemokines, and exosomes that impact every aspect of the tumor, including its response to treatment. It is believed that exosomal miRNAs facilitate intercellular signaling, which is essential for the development of cancer. The role of miRNAs and CAFs in the tumor microenvironment (TME) and carcinogenesis is reviewed in this paper. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines were used to perform a systematic review. Several databases, including Web of Science, Medline, Embase, Cochrane Library, and Scopus, were searched using the following keywords: CAFs, CAF, cancer-associated fibroblasts, stromal fibroblasts, miRNA, exosomal miRNAs, exosome and similar terms. We identified studies investigating exosomal miRNAs and CAFs in the TME and their role in carcinogenesis. A total of 12,572 papers were identified. After removing duplicates (n = 3803), 8774 articles were screened by title and abstract. Of these, 421 were excluded from further analysis. It has been reported that if exosomal miRNAs in CAFs are not functioning correctly, this may influence the secretory phenotype of tip cells and contribute to increased tumor invasiveness, tumor spread, decreased treatment efficacy, and a poorer prognosis. Under their influence, normal fibroblasts (NFs) are transformed into CAFs. Furthermore, they participate in metabolic reprogramming, which allows for fast proliferation of the cancer cell population, adaptation to growing energy demands, and the capacity to avoid immune system identification.

Breast cancer (BC) is the most prevalent cancer and the leading cause of death among women worldwide. The osteoprotegerin (OPG) cytokine, a decoy receptor for RANKL and a key player in bone homeostasis, has pro-and anti-carcinogenic effects in various types of cancer, including breast neoplasms. In the present study, we have shown that ectopic expression of OPG in breast epithelial/cancer cells promotes the pro-metastatic processes epithelial-to-mesenchymal transition (EMT), stemness, angiogenesis as well as the activation of breast stromal fibroblasts. Furthermore, proteomics analysis, which allows the identification and quantification of a plethora of known and unknown proteins, has shown a strong and significant correlation between OPG upregulation and the expression of proteins with functions in EMT and stemness. On the other hand, OPG knockdown in triple-negative breast cancer (TNBC) cells inhibited the formation of cancer stem cells. Importantly, while OPG upregulation significantly enhanced the resistance of luminal BC cells to cisplatin and docetaxel, OPG downregulation sensitized TNBC cells to these chemotherapeutic drugs. We have also shown that OPG negatively controls estrogen receptor α (ERα), and OPG upregulation correlated well with the expression of genes related to ER-negative claudin low cells. Collectively, these results show that OPG promotes stemness and the consequent chemoresistance of breast cancer cells.

The transcription factor regulatory factor X 7 (RFX7) has been identified as a tumor suppressor that is recurrently mutated in lymphoid cancers and appears to be dysregulated in many other cancers. RFX7 is activated by the well-known tumor suppressor p53 and regulates several other known tumor suppressor genes. However, what other factors regulate RFX7 and its target genes remains unclear. Here, reporter gene assays were used to identify that RFX7 regulates the tumor suppressor gene PDCD4 through direct interaction with its X-box promoter motif. We utilized mass spectrometry to identify factors that bind to DNA together with RFX7. In addition to RFX7, we also identified RFX5, RFXAP, RFXANK, and ANKRA2 that bind to the X-box motif in the PDCD4 promoter. We demonstrate that ANKRA2 is a bona fide direct p53 target gene. We used transcriptome analyses in two cell systems to identify genes regulated by ANKRA2, its sibling RFXANK, and RFX7. These results revealed that ANKRA2 functions as a critical cofactor of RFX7, whereas RFXANK regulates largely distinct gene sets.