Signaling Events Research Articles

Detection of Stress Corrosion Cracking in SS304 under Calcium Silicate Thermal Insulation Using Acoustic Emission Technique

Despite its remarkable structural strength, austenitic stainless steels such as SS304 are susceptible to stress corrosion cracking (SCC) under thermal insulation due to the synergism of cyclic loading and chloride-containing environments. This study aims to detect SCC for insulated SS304 samples using the acoustic emission technique (AET) as monitoring tool to characterize the various stages of SCC damage mechanism. As-received (AR) and sensitized (SEN) SS304 samples were prepared as per ASTM G30 and experimented with soluble chloride drip test under calcium silicate thermal insulation following ASTM C692. Both AR and SEN samples revealed SCC behavior correlated with measured acoustic signals. AR samples exhibited a single crack with low energetic signals, whereas SEN showed multiple cracks with higher energetic signal events. The difference can be attributed to microstructure change by heat sensitization and the enhancement of the corrosion environment under calcium silicate insulation when wetted by salt solution. The acoustic emission (AE) parameters were characterized and correlated with different stages of SCC phenomena, showing that AET is useful for predicting SCC to avoid catastrophic failures in industries.

Final CONUS Results on Coherent Elastic Neutrino-Nucleus Scattering at the Brokdorf Reactor

The CONUS experiment studies coherent elastic neutrino-nucleus scattering in four 1 kg germanium spectrometers. Low ionization energy thresholds of 210 eV were achieved. The detectors were operated inside an optimized shield at the Brokdorf nuclear power plant which provided a reactor antineutrino flux of up to 2.3×1013 cm−2 s−1. In the final phase of data collection at this site, the constraints on the neutrino interaction rate were improved by an order of magnitude as compared to the previous CONUS analysis. The new limit of less than 0.34 signal events kg−1 d−1 is within a factor 2 of the rate predicted by the standard model. This constraint is discussed in the context of conflicting measurements and results from another reactor neutrino experiment using similar technology. Published by the American Physical Society 2024

An Insight into the Role of IL-10 and Foamy Macrophages in Infectious Diseases.

Dysregulation of lipid homeostasis causes the deposition of lipids in the form of tiny droplets within foamy macrophages (FMs). In FMs, host-derived lipids aid in survival of various intracellular pathogens leading to sustained infection. In several infectious diseases, the transformation of macrophages into a foamy phenotype is linked to the presence of high IL-10, a potent immune-modulatory cytokine. This review aims to understand the role of IL-10 in the signaling events that are crucial in generation of FMs and highlights how various intracellular pathogens targets the IL-10-FM axis for successful establishment of infections. The review also briefly discusses how the IL-10-FM axis can be a target for developing novel therapeutic strategies to prevent intracellular infections.

Leveraging Evolutionary Immunology in Interleukin-6 and Interleukin-17 Signaling for Lung Cancer Therapeutics.

Lung cancer is among the most common instances of cancer subtypes and is associated with high mortality rates. Due to the availability of fewer therapies and delayed clinical investigations, the number of cancer incidences is rising dramatically. This is possibly an effect of immune modulations and chemotherapeutic drugs that raises cancer resistance. Among the list, IL-6 and IL-17 are host-derived paradoxical effectors that attune immune responses in malignant lung cells. Their excessive release in the cytokine milieu stabilizes immunosuppressive phenotypes, resulting in cellular perturbations. During tumor development, the significance of these molecules is reflected in their potential to regulate oncogenesis by initiating a myriad of signaling events that influence tumor growth and the metastatic ability of benign cancer cells. Moreover, their transactivation contributes to antiapoptotic mechanisms and favors cancer cell survival via constitutive expression of immunoregulatory molecules. Co-evolution and gene duplication events could be the major drivers behind cytokine evolution, which have prompted generic changes and, hence, the additive effect. The evolutionary model and statistical analysis provide evidence about the cytokines ancestral relationships and site-specific conservation, which is more convincing as both cytokines share cysteine-knot-like structures important in maintaining structural integrity. Funneling through the findings could help find residues that serve a catalytic role in immune functioning. Designing peptides or subunit vaccine formulations against those conserved residues could aid in combating lung cancer pathogenesis.

Mechanisms of Cbl-Mediated Ubiquitination of Proteins in T and Natural Killer Cells and Effects on Immune Cell Functions

Post-translational ubiquitination is an essential mechanism for the regulation of protein stability and function, which contributes to the regulation of the immune system. Cbl, an E3 ubiquitin ligase, is particularly well-characterized in the context of T and NK cell signaling, where it serves as a key regulator of receptor downstream signaling events and as a modulator of cell activation. Cbl promotes the proteasomal degradation of TCR/CD3 subunits as well as the protein kinases Fyn and Lck in T cells. Additionally, the scaffold protein linker for activation of T cells (LAT) is a universal target for Cbl-mediated ubiquitination and degradation in both T and NK cells. Recent findings suggest that CrkII-mediated ubiquitination and degradation of C3G by Cbl during early T cell activation may also be relevant to NK cell signaling. Given its role in modulating immune responses and its manageable impact on autoimmunity, Cbl is being investigated as a target for cancer immunotherapy. This review explores the ubiquitin ligase activity of Cbl and its implications for CAR T and NK cell immunotherapies.

High cell throughput, programmable fixation reveals the RNA and protein co-regulation with spatially resolved NFκB pseudo-signaling.

RNA translation to protein is paramount to creating life, yet RNA and protein correlations vary widely across tissues, cells, and species. To investigate these perplexing results, we utilize a time-series fixation method that combines static stimulation and a programmable formaldehyde perfusion to map pseudo-Signaling with Omics signatures (pSigOmics) of single-cell data from hundreds of thousands of cells. Using the widely studied nuclear factor kappa B (NFκB) mammalian signaling pathway in mouse fibroblasts, we discovered a novel asynchronous pseudotime regulation (APR) between RNA and protein levels in the quintessential NFκB p65 protein using single molecule spatial imaging. Prototypical NFκB dynamics are successfully confirmed by the rise and fall of NFκB response as well as A20 negative inhibitor activity by 90 min. The observed p65 translational APR is evident in both statically sampled timepoints and dynamic response gradients from programmable formaldehyde fixation, which successfully creates continuous response measurements. Finally, we implement a graph neural network model capable of predicting APR cell subpopulations from GAPDH RNA spatial expression, which is strongly correlated with p65 RNA signatures. Successful decision tree classifiers on Potential of Heat-diffusion for Affinity-based Trajectory Embedding embeddings of our data, which illustrate partitions of APR cell subpopulations in latent space, further confirm the APR patterns. Together, our data suggest an RNA-protein regulatory framework in which translation adapts to signaling events and illuminates how immune signaling is timed across various cell subpopulations.

Plant physiology: Plant stomata count on closure

The aperture of the stomatal pore is finely regulated by a range of external cues, and the underlying signalling events of this have been the subject of much investigation. A new study shows that elevation of cytosolic calcium is sufficient to induce stomatal closure and sheds light on the mechanisms underlying the regulation of stomatal aperture.

Roles for PKC signaling in chromaffin cell exocytosis

Chromaffin cells of the adrenal medulla have an important role in the sympathetic stress response. They secrete catecholamines and other hormones into the bloodstream upon stimulation by the neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP causes a long-lasting and robust secretory response from chromaffin cells. However, the cellular mechanisms by which PACAP causes secretion remain unclear. Our previous work showed that the secretory response to PACAP relies on signaling through phospholipase C ε (PLCε). The objective of this study was to clarify the role of signaling events downstream of PLCε. Here, it is demonstrated that a brief exposure of chromaffin cells to PACAP caused diacylglycerol (DAG) production – a process that was dependent on PLCε activity. DAG then activated protein kinase C (PKC), prompting its redistribution to the plasma membrane. PKC activation is important for the increases in cytosolic Ca2+ and exocytosis that are evoked by PACAP. Indeed, pharmacological inhibition of PKC with NPC 15437, a competitive inhibitor of DAG binding, significantly disrupted the secretory response. NPC 15437 application also eliminated PACAP-stimulated effects on the readily releasable pool size, the Ca2+ sensitivity of granule fusion, and the voltage-dependence of Ca2+ channel activation. Quantitative PCR revealed PKCβ, PKCε, and PKCμ to be highly expressed in the mouse chromaffin cell. Genetic knockdown of PKCβ and PKCε disrupted PACAP-evoked secretion, while knockdown of PKCμ had no measurable effect. This study highlights important roles for PKC signaling in a highly regulated pathway for exocytosis that is stimulated by PACAP.

The interaction of BDNF with estrogen in the development of hypertension and obesity, particularly during menopause.

The expression of BDNF in both neuronal and non-neuronal cells is influenced by various stimuli, including prenatal developmental factors and postnatal conditions such as estrogens, dietary habits, and lifestyle factors like obesity, blood pressure, and aging. Central BDNF plays a crucial role in modulating how target tissues respond to these stimuli, influencing the pathogenesis of hypertension, mitigating obesity, and protecting neurons from aging. Thus, BDNF serves as a dynamic mediator of environmental influences, reflecting an individual's unique history of exposure. Estrogens, on the other hand, regulate various processes to maintain overall physiological well-being. Through nuclear estrogen receptors (ERα, ERβ) and the membrane estrogen receptor (GPER1), estrogens modulate transcriptional processes and signaling events that regulate the expression of target genes, such as ERα, components of the renin-angiotensin system (RAS), and hormone-sensitive lipase. Estrogens are instrumental in maintaining the set point for blood pressure and energy balance. BDNF and estrogens work cooperatively to prevent obesity by favoring lipolysis, and counteractively regulate blood pressure to adapt to the environment. Estrogen deficiency leads to menopause in women with low central BDNF level. This review delves into the complex mechanisms involving BDNF and estrogen, especially in the context of hypertension and obesity, particularly among postmenopausal women. The insights gained aim to inform the development of comprehensive therapeutic strategies for these prevalent syndromes affecting approximately 68% of adults.

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo . Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

An early, novel arginine methylation of KCa3.1 attenuates subsequent T cell exhaustion.

T cell receptor (TCR) engagement initiates the activation process, and this signaling event is regulated in multifaceted ways. Nutrient availability in the immediate niche is one such mode of regulation 1-3 . Here, we investigated how the availability of an essential amino acid methionine (Met) and TCR signaling might interplay in the earliest events of T cell activation to affect subsequent T cell fate and function. We found that limiting Met during only the initial 30 minutes of CD8 + T cell activation increased Ca 2+ influx, Ca 2+ -mediated NFAT1 ( Nfatc2 ) activation, NFAT1 promoter occupancy, and T cell exhaustion. We identified changes in the protein arginine methylome during the initial 30 min of TCR engagement and discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, which regulates Ca 2+ -mediated NFAT1 signaling to ensure optimal activation. Ablation of arginine methylation in KCa3.1 led to increased NFAT1 activation, rendering T cells dysfunctional in murine tumour and infection models. Furthermore, acute Met supplementation at early stages reduced nuclear NFAT1 in tumour-infiltrating T cells and augmented their anti-tumour activity. Our findings identify a metabolic event occurring early after T cell activation that influences the subsequent fate of the cell.

Cell non-autonomous signaling through the conserved C. elegans glycoprotein hormone receptor FSHR-1 regulates cholinergic neurotransmission.

Modulation of neurotransmission is key for organismal responses to varying physiological contexts such as during infection, injury, or other stresses, as well as in learning and memory and for sensory adaptation. Roles for cell autonomous neuromodulatory mechanisms in these processes have been well described. The importance of cell non-autonomous pathways for inter-tissue signaling, such as gut-to-brain or glia-to-neuron, has emerged more recently, but the cellular mechanisms mediating such regulation remain comparatively unexplored. Glycoproteins and their G protein-coupled receptors (GPCRs) are well-established orchestrators of multi-tissue signaling events that govern diverse physiological processes through both cell-autonomous and cell non-autonomous regulation. Here, we show that follicle stimulating hormone receptor, FSHR-1, the sole Caenorhabditis elegans ortholog of mammalian glycoprotein hormone GPCRs, is important for cell non-autonomous modulation of synaptic transmission. Inhibition of fshr-1 expression reduces muscle contraction and leads to synaptic vesicle accumulation in cholinergic motor neurons. The neuromuscular and locomotor defects in fshr-1 loss-of-function mutants are associated with an underlying accumulation of synaptic vesicles, build-up of the synaptic vesicle priming factor UNC-10/RIM, and decreased synaptic vesicle release from cholinergic motor neurons. Restoration of FSHR-1 to the intestine is sufficient to restore neuromuscular activity and synaptic vesicle localization to fshr-1-deficient animals. Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects. Re-expression of FSHR-1 in other sites of endogenous expression, including glial cells and neurons, also restored some neuromuscular deficits, indicating potential cross-tissue regulation from these tissues as well. Genetic interaction studies provide evidence that downstream effectors gsa-1/GαS, acy-1/adenylyl cyclase and sphk-1/sphingosine kinase and glycoprotein hormone subunit orthologs, GPLA-1/GPA2 and GPLB-1/GPB5, are important for intestinal FSHR-1 modulation of the NMJ. Together, our results demonstrate that FSHR-1 modulation directs inter-tissue signaling systems, which promote synaptic vesicle release at neuromuscular synapses.

Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.

Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. To address these questions, we measured SPREAD activity with live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial (pHBE) cells, in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Airway epithelial cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD). Type 1 pro-inflammatory cytokines significantly increased the frequency of SPREADs, which coincided with epithelial barrier breakdown in differentiated pHBE cells. Furthermore, SPREADs correlated with IL-6 peptide secretion and the appearance of localized clusters of phospho-STAT3 immunofluorescence. To probe the mechanism of SPREADs, cells were co-treated with pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) or metabolic modulators (insulin, 2-deoxyglucose). Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence, implying that pro-inflammatory cytokines and glucose metabolism modulate SPREADs in human airway epithelial cells via secreted EGFR and IL6R ligands. We conclude that spatiotemporal ERK signaling plays a role in barrier homeostasis and dysfunction during inflammation of the airway epithelium. This novel signaling mechanism could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.

Deciphering Whether Illite, a Natural Clay Mineral, Alleviates Cadmium Stress in Glycine max Plants via Modulation of Phytohormones and Endogenous Antioxidant Defense System

Globally, cadmium (Cd) stress dramatically reduces agricultural yield. Illite, a natural clay mineral, is a low-cost, environmentally acceptable, new promising method of reducing the heavy metal (HM) stress of cereal crops. In research statistics, there is little research on stress tolerance behavior of Illite (IL) on an experimental soybean plant. In the present study, we took IL and examined it for tolerance to Cd, as well as for other plant-growth-promoting (PGP) characteristics in Glycine max (soybean). The results showed that applying clay minerals in different concentrations enhanced the level of SA (defense hormone) and reduced the level of ABA (stress hormone). Cd 1 mM significantly reduces plant growth by altering their morphological characteristics. However, the application of IL significantly enhanced the seedling characteristics, such as root length (RL), 29.6%, shoot length (SL), 14.5%, shoot fresh biomass (SFW), 10.8%, and root fresh biomass (RFB), 6.4%, in comparison with the negative control group. Interestingly, IL 1% also enhanced the chlorophyll content (C.C), 15.5%, and relative water content (RWC), 12.5%, in all treated plants. Moreover, it resulted in an increase in the amount of superoxide dismutase (SOD), phenolics, and flavonoids in soybean plants, while lowering the levels of peroxidase (POD) and H2O2. Furthermore, compared to control plants, soybean plants treated with the Illite exhibited increased Si absorption and lower Cd levels, according to inductively coupled plasma mass spectrometry (ICP-MS). Thus, the IL can operate as an environmentally beneficial biofertilizer and sustainable approach under Cd stress by promoting plant development by activating signaling events.

The vacuolar K+/H+ exchangers and calmodulin-like CML18 constitute a pH-sensing module that regulates K+ status in Arabidopsis.

Shifts in cytosolic pH have been recognized as key signaling events and mounting evidence supports the interdependence between H+ and Ca2+ signaling in eukaryotic cells. Among the cellular pH-stats, K+/H+ exchange at various membranes is paramount in plant cells. Vacuolar K+/H+ exchangers of the NHX (Na+,K+/H+ exchanger) family control luminal pH and, together with K+ and H+ transporters at the plasma membrane, have been suggested to also regulate cytoplasmic pH. We show the regulation of vacuolar K+/H+ exchange by cytoplasmic pH and the calmodulin-like protein CML18 in Arabidopsis. The crystal structure and physicochemical properties of CML18 indicate that this protein senses pH shifts. Interaction of CML18 with tonoplast exchangers NHX1 and NHX2 was favored at acidic pH, a physiological condition elicited by K+ starvation in Arabidopsis roots, whereas excess K+ produced cytoplasmic alkalinization and CML18 dissociation. These results imply that the pH-responsive NHX-CML18 module is an essential component of the cellular K+- and pH-stats.

Anti-Inflammatory Effects of Cordyceps Cs-HK1 Fungus Exopolysaccharide on Lipopolysaccharide-Stimulated Macrophages via the TLR4/MyD88/NF-κB Pathway.

Chronic inflammation is a common factor in the pathological processes of multiple human diseases. EPS-LM, an exopolysaccharide (EPS) from the Cordyceps sinensis fungus Cs-HK1, has shown notable anti-inflammatory activities in previous studies. This study aimed to investigate the major signaling events mediating the anti-inflammatory effects of EPS-LM in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cell culture. EPS-LM treatment significantly reduced LPS-induced production of pro-inflammatory mediators, including nitric oxide (NO) and reactive oxygen species (ROS). It also suppressed the expression levels of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), subsequently delaying the translocation of nuclear factor-kappa B (NF-κB) to the nucleus. Additionally, co-immunoprecipitation (Co-IP) experiments demonstrated that EPS-LM inhibited the binding of TLR4 to MyD88. The ability of EPS-LM to inhibit the TLR4/MyD88/NF-κB pathway, coupled with its capacity to reduce oxidative stress, underscores its multifaceted anti-inflammatory effects. These effects render EPS-LM as a promising candidate for the comprehensive management of various inflammatory and oxidative stress-related conditions, protecting against cell damage.

Colorectal carcinoma progression is not influenced by the pseudokinase PEAK1

The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1−/− mice in the Apcfl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1’s impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.

Towards New Anti-inflammatory Agents: Design, Synthesis and Evaluation of Molecules Targeting XIAP-BIR2.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20c. The ability of compound 20c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

TMET-28. RECIPROCAL LINKS BETWEEN METHIONINE METABOLISM, DNA REPAIR AND THERAPY RESISTANCE IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance.Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor-specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

PRMT1-mediated methylation of ME2 promotes hepatocellular carcinoma growth by inhibiting ubiquitination

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.