Cell Stress最新文献

In a recent issue in Nature Cell Biology, Sung Min Son et al. unveil a novel layer in the regulation of the mTORC1/autophagy axis by EP300 which can undergo nucleocytoplasmic shuttling in response to alterations in nutrient availability. The study highlights that, in Hutchinson-Gilford progeria syndrome, overabundant cytoplasmic EP300 results in mTORC1 hyperactivation and impaired autophagy, potentially contributing to premature and accelerated aging.

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health ("psychosocial adaptation") and as an additional stratum ("psychosocial interactions"), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.

Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy.

Adoptive cell therapy (ACT) can successfully treat hematopoietic cancers but lacks efficacy against solid tumors. This is due to insufficient T cell infiltration, high tumor heterogeneity, frequent antigen loss with subsequent tumor escape, and the immunosuppressive tumor microenvironment (TME). Alternative methods to boost the anticancer efficacy of adoptively transferred cells are actively pursued. Among adjuvants that are utilized to stimulate anticancer immune responses, ligands of the stimulator of interferon genes (STING) pathway have received increasing attention. STING activation can trigger dendritic cell (DC) activation and endogenous immune responses, thereby preventing tumor escape. Activation of the STING pathway in the context of ACT was accordingly associated with improved T cell trafficking and persistence in the TME combined with the reduced presence of immunosuppressive cells. Recent findings also suggest cell-intrinsic effects of STING ligands on T cells. Activation of the STING signaling pathway was in this regard shown to enhance effector functions of CD4⁺ and CD8⁺ T cells, suggesting that the STING signaling could be exploited to harness T cell anticancer functions. In this review, we will discuss how the STING signaling can be used to enhance the anticancer efficacy of ACT.

Chromatin assembly and the establishment of sister chromatid cohesion are intimately connected to the progression of DNA replication forks. Here we examined the genetic interaction between the heterotrimeric chromatin assembly factor-1 (CAF-1), a central component of chromatin assembly during replication, and the core replisome component Ctf4. We find that CAF-1 deficient cells as well as cells affected in newly-synthesized H3-H4 histones deposition during DNA replication exhibit a severe negative growth with ctf4Δ mutant. We dissected the role of CAF-1 in the maintenance of genome stability in ctf4Δ yeast cells. In the absence of CTF4, CAF-1 is essential for viability in cells experiencing replication problems, in cells lacking functional S-phase checkpoint or functional spindle checkpoint, and in cells lacking DNA repair pathways involving homologous recombination. We present evidence that CAF-1 affects cohesin association to chromatin in a DNA-damage-dependent manner and is essential to maintain cohesion in the absence of CTF4. We also show that Eco1-catalyzed Smc3 acetylation is reduced in absence of CAF-1. Furthermore, we describe genetic interactions between CAF-1 and essential genes involved in cohesin loading, cohesin stabilization, and cohesin component indicating that CAF-1 is crucial for viability when sister chromatid cohesion is affected. Finally, our data indicate that the CAF-1-dependent pathway required for cohesion is functionally distinct from the Rtt101-Mms1-Mms22 pathway which functions in replicated chromatin assembly. Collectively, our results suggest that the deposition by CAF-1 of newly-synthesized H3-H4 histones during DNA replication creates a chromatin environment that favors sister chromatid cohesion and maintains genome integrity.

Non-invasive imaging of tumors expressing reporter transgenes is a popular preclinical method for studying tumor development and response to therapy in vivo due to its ability to distinguish signal from tumors over background noise. However, the utilized transgenes, such as firefly luciferase, are immunogenic and, therefore, impact results when expressed in immune-competent hosts. This represents an important limitation, given that cancer immunology and immunotherapy are currently among the most impactful areas of research and therapeutic development. Here we present a non-immunogenic preclinical tumor imaging approach. Based on the expression of murine sodium iodide symporter (mNIS), it facilitates sensitive, non-invasive detection of syngeneic tumor cells in immune-competent tumor models without additional immunogenicity arising from exogenous transgenic protein or selection marker expression. NIS-expressing tumor cells internalize the gamma-emitting [^99mTc]pertechnetate ion and so can be detected by SPECT (single photon emission computed tomography). Using a mouse model of pancreatic ductal adenocarcinoma hepatic metastases in immune-competent C57BL/6 mice, we demonstrate that the technique enables the detection of very early metastatic lesions and longitudinal assessment of immunotherapy responses using precise and quantifiable whole-body SPECT/CT imaging.

Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8⁺ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.

The continuous use of antibiotics is associated with the spread of antimicrobial resistances and the not yet clear link to cancer development. Many conventional antibiotics have already shown different effects on a variety of cancer types raising questions for their rational use in cancer. However, discrepancy in the observed trend for some antibiotics reducing cancer development and being associated with higher risk of cancer underscores the lack of understanding the complex link between antibiotics and cancer. Here, we briefly summarize the possible antibiotic-mediated effects on cancer and conclude that those effects can be direct via i) specific targeting of tumor/cancer, ii) antimicrobial activity and iii) immunomodulatory activity whereby iv) indirectly caused effects primarily affect immune equilibrium between bacteria, cancer and immune cells. Furthermore, we also conclude that there is a great need for bulk profiling, comprehensive screening programs in all countries and in-depth studies to understand the risks and benefits of antibiotic use.

Zearalenone (ZEA) exposure has carcinogenic effects on human and animal health by exhibiting intestinal, hepatic, and renal toxicity. At present, the underlying mechanisms on how ZEA induces apoptosis and damage to tissues still remain unclear. In this study, we aimed to identify genes that modulate the cellular response to ZEA using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening, and further validate novel gene functions to elucidate molecular mechanisms underlying particular biological processes in vivo and in vitro. Two ZEA-resistant cell lines, designated Ov-KCNJ4 and Ov-KCNJ12, were yielded by CRISPR activation screening which had significant changes in ZEA resistance and growth rates. Results showed that ZEA could interact with the cell membrane proteins KCNJ4 and KCNJ12, inducing cell cycle arrest, disruption of DNA replication and base excision repair. Overexpression of KCNJ4 and KCNJ12 was involved in ZEA resistance by regulating cell cycle to neutralize toxicity, sustaining mitochondrial morphology and function via attenuating the damage from oxidative stress in the KCNJ4-mitoK_ATP pathway. In vivo experiments showed that AAV-KCNJ4 delivery significantly improved ZEA-induced renal impairment and increased antioxidative enzyme activity by improving mitochondrial function. Our findings suggest that increasing potassium channel levels may be a putative therapeutic target for mycotoxin-induced damage.