Cell Communication and Signaling最新文献

{"title":"Synergic action of MicroRNAs and Wnts delivered by motor neuron EVs in promoting AChR clustering.","authors":"Rachele Agostini, Paola Ceccaroli, Emanuela Polidori, Manuela Ferracin, Ilaria Pace, Serena Maggio, Andrea Cioccoloni, Michela Battistelli, Giulia Matacchione, Matilde Sbriscia, Fabiola Olivieri, Fabrizia Cesca, Vilberto Stocchi, Michele Guescini","doi":"10.1186/s12964-025-02312-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02312-x","url":null,"abstract":"<p><strong>Background: </strong>The neuromuscular junction (NMJ) establishment occurs through complex communication events between motor neurons and muscle fibers; however, the molecular mechanisms leading to NMJ formation have yet to be fully elucidated. Little is known about the significance of extracellular vesicles (EVs) in mediating the interaction between motor neurons and muscle fiber in the NMJ establishment; this study investigates the role of motor neuron-derived EVs during the earliest stages of NMJ formation.</p><p><strong>Methods: </strong>NSC-34 cells have been used as a model of motor neurons; EVs have been isolated during neurite development using a serial ultracentrifugation protocol specifically adjusted to isolate large and small EVs. Isolated EVs were quantified through Nanoparticles Tracking Assay and characterized by Western Blot and TEM analyses. The microRNA (miRNA) cargo of EV subpopulations was identified by small-RNA sequencing and the predicted miRNA downstream targets were investigated.</p><p><strong>Results: </strong>NGS analysis of small RNAs carried by NSC-34-derived EVs identified a total of 245 EV specific miRNAs, most of which are up-regulated in NSC-34 cells and EVs during neurite stretching. Target prediction analysis evidenced how these miRNAs synergically target the Wnt signaling pathway. Moreover, we found that NSC-34-derived EVs carry Wnt proteins, including Wnt11, Wnt4 and Wnt3a. Since several studies suggested a role for the Wnt-associated signaling network in NMJ formation, we investigated the potential role of NSC-34 EVs in NMJ development and demonstrated that EV administration to myotubes increases acetylcholine receptor (AChR) cluster formation, as revealed by immunofluorescence staining with α-bungarotoxin. Moreover, myotube treatment with NSC-34-derived EVs led to GSK3β and JNK phosphorylation, followed by β-catenin nuclear translocation, suggesting that neuron-derived EVs can induce AChR clustering through Wnt pathway activation.</p><p><strong>Conclusion: </strong>These data demonstrate that EVs released from differentiated motor neurons carry multimodal signals, miRNAs, and Wnts, which can stimulate AChR clustering in myotubes, a fundamental preparatory stage for NMJ formation. These new data highlight that EVs may play a role in the NMJ establishment and function under physiological and pathological conditions, particularly neurodegenerative diseases.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"360"},"PeriodicalIF":8.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-fat diet impairs microbial metabolite production and aggravates influenza A infection.","authors":"Franziska Hornung, Harini K SureshKumar, Laura Klement, Yasmina Reisser, Christoph Wernike, Vivien Nischang, Paul M Jordan, Oliver Werz, Carsten Hoffmann, Bettina Löffler, Stefanie Deinhardt-Emmer","doi":"10.1186/s12964-025-02367-w","DOIUrl":"https://doi.org/10.1186/s12964-025-02367-w","url":null,"abstract":"<p><strong>Background: </strong>Alterations in the gut microbiom can significantly impact various regions in the human body, including the pulmonary tract. This study investigates alterations in the gut microbiome during a high-fat diet (HFD), particularly short-chain fatty acids (SCFAs), and how these metabolites affect lung infection caused by Influenza A virus (IAV).</p><p><strong>Methods: </strong>We used a HFD-mouse model to evaluate gut microbiota composition, SCFA levels, and pulmonary outcomes following IAV infection. Microbial changes were analyzed via taxonomic and functional profiling and SCFA levels were measured from non-obese and obese serum donors. Ultimately, acetate's effects were tested ex vivo in human precision-cut lung slices (PCLS) and in vitro in pulmonary epithelial cells. Mechanistic studies investigated the involvement of the SCFA receptor free fatty acid receptor 2 (FFAR2) and intracellular antiviral pathways.</p><p><strong>Results: </strong>Our data indicates an increased Firmicutes/Bacteroidetes ratio of the gut microbiome and an altered carbohydrate metabolism, leading to reduced SCFA production. Infected HFD mice showed increased IAV titers and sustained microbial alterations. Interestingly, acetate demonstrated antiviral effects in both the human PCLS model and pulmonary cells with an reduced viral replication. These effects depended on FFAR2, which also acts as an IAV co-receptor, as acetate treatment led to FFAR2 internalization and influenced host cell metabolism in our in vitro data.</p><p><strong>Conclusion: </strong>HFD alters the SCFA production, reducing acetate levels in the gut microbiome. This reduction may lead to higher viral loads and worsened disease in HFD mice infected with IAV. Our findings indicate that acetate has antiviral effects during IAV infection in both a human ex vivo lung model and pulmonary epithelial cells. Here, acetate prevents viral entry and affects the cellular metabolic state and antiviral response. Understanding these mechanisms could provide new targets for preventing and treating viral infections in individuals with diet-related health issues.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"359"},"PeriodicalIF":8.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Notch signaling by multiple Ankyrin repeat containing protein Mask.","authors":"Bappi Sarkar, Jyoti Singh, Dipti Verma, Mousumi Mutsuddi, Ashim Mukherjee","doi":"10.1186/s12964-025-02190-3","DOIUrl":"10.1186/s12964-025-02190-3","url":null,"abstract":"<p><strong>Background: </strong>Notch pathway is an evolutionarily conserved, highly pleiotropic signaling system that governs diverse developmental processes. Its diverse functions are attributed to the intricate regulatory mechanisms that finely tune the pathway. While several known elements contribute to maintaining cellular homeostasis by modulating Notch signaling, many unidentified components likely play significant roles in its regulation, necessitating further exploration.</p><p><strong>Methods: </strong>To identify novel regulators of Notch-intracellular domain (Notch-ICD), we carried out a yeast two-hybrid screen and identified Multiple Ankyrin repeat single KH domain containing protein (Mask) as an interacting partner of Notch-ICD. Physical interaction between these two proteins was further validated by co-immunoprecipitation experiments. Moreover, cellular studies using immunocytochemistry reveals that Mask plays important role in Notch turnover and protect from degradation. To inhibit lysosomal degradation, chloroquine was introduced in the food at a concentration of 1 mg/ml.</p><p><strong>Results: </strong>Immunocytochemical analyses revealed that Notch and Mask co-localised within the same subcellular compartments. Different alleles of mask showed strong genetic interactions with Notch pathway components in transheterozygous combinations. Loss- and gain-of-function studies of Mask demonstrated that it plays a regulatory role in Notch signaling. Specifically, the absence of Mask results in downregulation of Notch target genes, although it does not significantly affect endogenous Notch protein levels. Our data suggest that Mask positively regulates Notch signaling by stabilizing Notch-ICD and protecting it from lysosomal degradation. Treatment with 1 mg/ml chloroquine can mitigate the Mask loss-mediated Notch intracellular domain degradation. This study presents a novel mode of Notch signaling regulation mediated by the Ankyrin repeat-containing protein Mask.</p><p><strong>Conclusion: </strong>Here we provide evidence that Mask physically binds with Notch-ICD and positively regulates Notch signaling pathway by protecting it from degradation. Mask genetically interacts with Notch and Notch pathway components and absence of Mask affects the Notch signaling pathway thus it may control the hyper activation of the signaling.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"358"},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of adiponectin and its receptors AdipoR1/2 in inflammatory bowel disease.","authors":"Qiuyan Zhu, Xiaoli Jia, Shupeng Li, Jinxing Feng","doi":"10.1186/s12964-025-02359-w","DOIUrl":"10.1186/s12964-025-02359-w","url":null,"abstract":"<p><p>Intake of nutrients and water from diet to maintain life, a typical physiological function of gut, is highly dependent on the extensive immune network, whose imbalance is easy to induce inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Clinical strategies to completely cure IBD are poor, so it is urgent to develop novel drugs or targets. Adiponectin (APN), an adipokine from adipocytes, regulates energy metabolism and immune response. High levels APN are inversely associated with CD severity UC colonic fibrosis. However, the mechanism by which APN interferes with IBD remains unclear. This review aims to analyze correlation and molecular mechanism between APN and IBD. APN and AdipoR2 proteins are highly expressed in colon which is a primary organ of IBD, and the target intersection of APN and IBD is huge. APN may interfere with lipid metabolism in IBD individuals through AdipoR1/2, but regulates neural and peripheral immune by AdipoR1 but not AdipoR2 and mediates nutritional and energy homeostasis through AdipoR2 rather than AdipoR1. Besides, APN mediates CRP and IL-6 through AdipoR1/2, AMPK and TNF-α through AdipoR1 and PI3K-Akt, PPARA and PPARG through AdipoR2 to affect IBD progression, which depends on direct interaction between APPL1 and AdipoR1/2. Unexpectedly, AMPK and TNF-α may also interact directly with AdipoR1. APN regulates CD through AdipoR1/2-metabolism process and UC through AdipoR1-inflammation axis or AdipoR2-fibrosis process. APN analogues or AdipoRon which is a dual agonist of AdipoR1/2 potentially reduces colonic fibrosis in UC and fistulae in CD, promotes mucosal healing, repairs intestinal microbiota homeostasis and increases autophagy to alleviate IBD symptoms by weakening TNF-α, IL-6, NLRP3, TGFB1 activities and aggrandizing P-AKT, PPARA, PPARG, INS, IRS1/2, IGF-1, TIMP1, NOD2, SIRT1 levels.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"356"},"PeriodicalIF":8.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal inflammation and microbiota modulation impact cochlear function: emerging insights in gut-ear axis.","authors":"Anna Pisani, Valentina Petito, Fabiola Paciello, Valeria Emoli, Letizia Masi, Veronica Mohamed Hizam, Pierluigi Puca, Raffaele Montuoro, Federica Del Chierico, Lorenza Putignani, Claudio Grassi, Jacopo Galli, Maurizio Taglialatela, Maria Emiliana Caristo, Gianluca Ianiro, Loris Riccardo Lopetuso, Giovanni Cammarota, Antonio Gasbarrini, Anna Rita Fetoni, Franco Scaldaferri","doi":"10.1186/s12964-025-02338-1","DOIUrl":"10.1186/s12964-025-02338-1","url":null,"abstract":"<p><strong>Background: </strong>Although several evidence demonstrates a \"gut-microbiota-brain axis\", suggesting a bidirectional communication between gut microbiota and the central nervous system, less is known about a possible link between the gut and the peripheral nervous system, including the inner ear.</p><p><strong>Methods: </strong>Here, we investigated the impact of intestinal inflammation and the modulation of gut microbiota through fecal microbiota transplantation on hearing sensitivity. Female C57BL/6 mice were assigned to four groups: control (Ctrl), DSS-induced colitis (DSS), FMT from patients with active ulcerative colitis (FMT aUC), and FMT from patients with ulcerative colitis in remission (FMT rUC). Auditory function was evaluated by auditory brainstem responses (ABR). Morphological and molecular analyses on cochlear tissues were performed using immunofluorescence, histological staining, and Western blot to assess inflammation, oxidative stress, and blood-labyrinth barrier integrity. Donor microbiota composition was characterized by 16S rRNA sequencing, and systemic inflammation was evaluated by measuring serum lipopolysaccharide (LPS) levels.</p><p><strong>Results: </strong>We found that intestinal dysbiosis is associated with functional, morphological, and molecular alterations in the cochlea, such as increased oxidative stress, inflammation, and altered blood-labyrinth barrier permeability. This leads to macrophage infiltration and immune response activation through the MyD88/NF-κB pathway. Notably, these effects were exacerbated by FMT from subjects with aUC, while FMT from patients with rUC provided a protective effect on cochlear functions.</p><p><strong>Conclusions: </strong>Overall, our findings suggest that gut inflammation, microbiota alteration, or its therapeutic modulation can impact inner ear pathology: worsening gut inflammatory status negatively affects hearing sensitivity, while the restoration of gut microbiota positively impacts auditory function.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"357"},"PeriodicalIF":8.2,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanobiology of extracellular matrix: a focus on thrombospondins.","authors":"Ying Zhao, Ting Lei, Xin Ge, Liumeizi Fan, Yinbin He, Zhou Yu, Sheng Hu","doi":"10.1186/s12964-025-02365-y","DOIUrl":"10.1186/s12964-025-02365-y","url":null,"abstract":"<p><p>Mechanosensitive thrombospondins (TSPs), a class of extracellular matrix (ECM) glycoproteins, have garnered increasing attention for their pivotal roles in transducing mechanical cues into biochemical signals during tissue adaptation and disease progression. This review delineates the context-dependent functions of TSP isoforms in cardiovascular homeostasis maintenance, cardiovascular remodeling, musculoskeletal adaptation, and pathologies linked to ECM stiffening, including fibrosis and tumorigenesis. Mechanistically, biomechanical stimuli regulate the expression of TSPs, enabling their interaction with transmembrane receptors and the activation of downstream effectors to orchestrate cellular responses. Under physiological mechanical stimuli, TSP-1 exhibits low-level expression, contributing to the maintenance of cardiovascular homeostasis. Conversely, under pathological mechanical stimuli, upregulated TSP-1 expression activates downstream signaling pathways. This leads to aberrant migration, proliferation, adhesion of cardiovascular cells, and collagen deposition, ultimately resulting in diseases including but not limited to atherosclerosis, pulmonary arterial hypertension (PAH), and myocardial fibrosis. In load-bearing musculoskeletal tissues, TSP-1 facilitates the mechanical adaptation of skeletal muscle and promotes cortical bone formation, whereas TSP-2 regulates chondrogenic differentiation. Within fibrotic and neoplastic tissues characterized by altered matrix stiffness, TSP-1 and - 2 exacerbates tissue fibrosis and tumor progression through transforming growth factor-β (TGF-β)-mediated signaling pathways. These findings establish TSPs as critical mechanochemical switches that govern tissue homeostasis and maladaptation. Clinically, the isoform-specific expression patterns of TSPs correlate with disease severity in atherosclerosis, osteoarthritis, and fibrotic tissues, highlighting their potential as mechanobiological biomarkers. Therapeutically, targeting force-sensitive TSP-receptor interfaces or mimicking their conformational changes under mechanical loading offers innovative strategies for treating mechanopathologies. This review provides a framework for understanding TSP-mediated mechanotransduction across scales, bridging molecular insights for translational applications in mechanopharmacology and ECM-targeted regenerative therapies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"354"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2.","authors":"Qingyi Hu, Qianzhi Chen, Wen Yang, Anwen Ren, Jie Tan, Tao Huang","doi":"10.1186/s12964-025-02356-z","DOIUrl":"10.1186/s12964-025-02356-z","url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective targeted therapies and the high likelihood of acquired resistance, triple-negative breast cancer (TNBC) remains one of the deadliest cancers affecting women globally. Investigating the mechanism underlying TNBC's resistance to platinum-based chemotherapy and identifying new therapeutic targets are urgent priorities.</p><p><strong>Methods: </strong>The expression level of GPX3, cisplatin sensitivity, and ROS production were compared across three TNBC cell lines to elucidate the relationship between GPX3 and platinum resistance. RNA sequencing and bioinformatics analyses of GPX3 knockdown cells revealed its regulation of stress-related signaling pathways and TGFB1. The regulation of TGFB1 by GPX3 was further investigated using Western blotting, RNA interference, confocal microscopy, and inhibitor treatments. The correlation between the expression level of GPX3, TGFB1, and ZEB2 was analyzed using breast cancer microarrays and the TCGA database. The effect of GPX3 on platinum sensitivity in TNBC was studied using a mouse xenograft model.</p><p><strong>Results: </strong>GPX3 expression was upregulated in more invasive TNBC cells, promoting resistance to cisplatin-based chemotherapy. RNA sequencing revealed that the deletion of GPX3 resulted in a decrease in gene expression patterns associated with pro-tumor signaling pathways. Validation experiments confirmed that the upregulation of TGFB1 in acquired cisplatin resistance is highly dependent on GPX3. Further investigation revealed that the TGFB1-ZEB2 axis mediated platinum resistance and metastasis through epithelial-mesenchymal transition (EMT). Additionally, platinum treatment increased GPX3 and TGFB1 expression and secretion, and their depletion enhanced platinum sensitivity in TNBC cells. We identified the GPX3-TGFB1-ZEB2 regulatory axis and found a positive correlation in the expression of all three in clinical samples. Our study also demonstrated that GPX3 knockdown inhibited TNBC tumor growth in platinum-treated mouse models.</p><p><strong>Conclusions: </strong>This study reveals the signaling pathway mediated by GPX3-TGFB1-ZEB2 and its role in acquired platinum resistance and EMT in TNBC. Our findings suggest that GPX3 is a promising biomarker and potential therapeutic target for the diagnosis, treatment, and prognosis of high-risk TNBC patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"355"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACACA depletion activates the cPLA2-arachidonic acid-NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer.","authors":"Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Yongding Wu, Huijing Tan, Hongwei Luo, Huichan He, Jiarun Lai, Weide Zhong","doi":"10.1186/s12964-025-02363-0","DOIUrl":"10.1186/s12964-025-02363-0","url":null,"abstract":"<p><strong>Background: </strong>Acetyl-CoA carboxylase alpha (ACACA) is a key enzyme in fatty acid biosynthesis and a proposed therapeutic target in prostate cancer. However, its role in androgen receptor-independent prostate cancer (ARIPC), an aggressive and treatment-resistant subtype, remains unclear. This study aimed to investigate the effects of ACACA depletion on ARIPC, with a focus on inflammation and metastasis.</p><p><strong>Methods: </strong>ACACA expression patterns were analyzed across multiple metastatic castration-resistant prostate cancer (mCRPC) datasets. In ARIPC cell lines, ACACA was inhibited via both shRNA and the pharmacological inhibitor TOFA. Transcriptomic, metabolomic, and single-cell RNA sequencing data were used to identify downstream changes. Inflammatory signaling was assessed by qPCR, western blotting, and immunofluorescence. Cell migration was evaluated via wound healing and transwell assays, and the metastatic potential was examined in a mouse tail vein injection model. The roles of arachidonic acid (AA), cytosolic phospholipase A2 (cPLA2), and NF-κB signaling were further tested through targeted inhibition.</p><p><strong>Results: </strong>ACACA expression was reduced in ARIPC and was negatively correlated with inflammatory pathways. Its inhibition upregulated proinflammatory cytokines and chemokines, elevated AA and eicosanoid levels, and increased cPLA2 expression. Single-cell RNA sequencing confirmed NF-κB signaling enrichment in ACACA-low tumor cells. Mechanistically, elevated AA activated NF-κB signaling. ACACA depletion enhanced cell migration and metastasis, along with macrophage infiltration. Inhibiting cPLA2 or NF-κB signaling reversed these effects.</p><p><strong>Conclusions: </strong>This study reveals a previously unrecognized tumor-promoting effect of ACACA depletion in ARIPC. Targeting ACACA in this context enhances inflammation and metastasis via arachidonic acid-mediated activation of NF-κB signaling. These findings highlight a context dependent, tumor-promoting role of ACACA inhibition and underscore the need for combinational strategies to avoid potential adverse outcomes in metabolic therapies.</p><p><strong>Trial registration: </strong>Not applicable.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"352"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing P2Y₁₂ and P2Y₁₃ receptors rehabilitates the ADP-induced P2Y₁-mediated osteogenic commitment of post-menopausal mesenchymal stromal cells.","authors":"Catarina Bessa-Andrês, Rui Pinto-Cardoso, Maria Adelina Costa, Fátima Ferreirinha, José Marinhas, Rolando Freitas, Rui Lemos, Diogo Catelas, Adélio Vilaça, António Oliveira, Paulo Correia-de-Sá, José Bernardo Noronha-Matos","doi":"10.1186/s12964-025-02355-0","DOIUrl":"10.1186/s12964-025-02355-0","url":null,"abstract":"<p><strong>Background: </strong>Participation of ADP-sensitive metabotropic P2Y₁, P2Y₁₂ and P2Y₁₃ receptors in human osteogenesis is controversial. Here, we investigated the variations in the expression and bone-forming properties of the P2Y₁R in osteogenic-differentiating bone marrow-derived mesenchymal stromal cells (BM-MSCs) isolated from post-menopausal (Pm) women. We also tested whether observed P2Y₁-related functional deficits result from the crosstalk with co-localized P2Y₁₂ and P2Y₁₃ receptors.</p><p><strong>Methods: </strong>Pm BM-MSCs were cultured in an osteogenic-inducing medium in either the absence or presence of the selective P2Y₁ receptor agonist, MR2365; this compound was applied alone or after cells' incubation with selective P2Y₁₂ and P2Y₁₃ receptor antagonists or short hairpin RNAs designed to silence P2Y₁₂ or P2Y₁₃ receptors gene expression.</p><p><strong>Results: </strong>BM-MSCs present immunoreactivity against all ADP-sensitive P2Y receptor subtypes, but their relative density varied among different Pm women and with the time of the cells in the culture. The P2Y₁receptor agonist increased the alkaline phosphatase activity and bone nodule formation in BM-MSCs originating from a younger female, but it failed to promote the osteogenic differentiation of BM-MSCs from Pm women unless P2Y₁₂ or P2Y₁₃ receptors are blocked with AR-C66096 and MRS211, respectively. Silencing the P2Y₁₃, but not the P2Y₁₂, receptor gene expression restored the P2Y₁-mediated osteogenic commitment of Pm BM-MSCs. The P2Y₁ receptor agonist failed to elicit [Ca²⁺]_i transients inside Pm BM-MSCs except after acute cholesterol depletion and lipid rafts disruption with methyl-β-cyclodextrin to prevent the P2Y₁/P2Y₁₃ receptors interplay.</p><p><strong>Conclusions: </strong>Thus, personalized offsetting the activity and/or expression of P2Y₁₃ receptor (and P2Y₁₂) may be a good strategy to rehabilitate the P2Y₁-mediated osteogenic potential of BM-MSCs and to reduce the fracture risk in Pm women.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"353"},"PeriodicalIF":8.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.","authors":"Uğur Kahya, Vasyl Lukiyanchuk, Ielizaveta Gorodetska, Matthias M Weigel, Ayşe Sedef Köseer, Berke Alkan, Dragana Savic, Annett Linge, Steffen Löck, Mirko Peitzsch, Ira-Ida Skvortsova, Mechthild Krause, Anna Dubrovska","doi":"10.1186/s12964-025-02344-3","DOIUrl":"10.1186/s12964-025-02344-3","url":null,"abstract":"<p><strong>Background: </strong>Metabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.</p><p><strong>Methods: </strong>The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. γH2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.</p><p><strong>Results: </strong>A siRNA-mediated knockdown of Gln transporters SLC1A5, SLC7A5, and SLC38A1 resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters SLC1A5, SLC7A5, or SLC38A1 induces expression of NUPR1, a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from NUPR1 knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.</p><p><strong>Conclusions: </strong>Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"351"},"PeriodicalIF":8.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}