Cell Communication and Signaling最新文献

{"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}

{"title":"Long interspersed nuclear element 1 methylation in non-small cell lung cancer: implications for diagnosis, prognosis, and therapeutic targeting.","authors":"Dileesha Prabani Wanasundara Arachchillage, Wanvisa Udomsinprasert","doi":"10.1186/s12964-025-02343-4","DOIUrl":"10.1186/s12964-025-02343-4","url":null,"abstract":"<p><p>Long interspersed nucleotide element 1 (LINE1), the most abundant repetitive element in the human genome, plays a crucial role in genomic instability. Aberrant LINE1 activation, primarily regulated by DNA methylation, is a hallmark of cancer. Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer worldwide, continues to pose significant challenges due to the invasiveness, high cost, and susceptibility to false positives of current diagnostic methods, as well as the emergence of treatment resistance. This review highlights the potential of LINE1 methylation as a biomarker for NSCLC, offering novel insights into its role in diagnosis, prognosis, and therapeutic strategies. Recent studies uncovered that LINE1 hypomethylation was strongly associated with poor overall survival, suggesting its utility as both a prognostic marker and a therapeutic target. However, further research is required to elucidate its precise regulatory mechanisms in LINE1 retrotransposition and to evaluate its potential as a non-invasive biomarker for improving NSCLC management.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"350"},"PeriodicalIF":8.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692528","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":"HAX1 inhibits apoptosis and promotes maturation of neutrophils.","authors":"Hanwei Yue, Guiying Shi, Jiaming Tang, Xinyue Li, Lin Bai","doi":"10.1186/s12964-025-02353-2","DOIUrl":"10.1186/s12964-025-02353-2","url":null,"abstract":"<p><p>As the diverse functions of neutrophils continue to be uncovered, elucidating the molecular mechanisms that regulate their differentiation, development, and apoptosis has become crucial for overcoming limitations in the treatment of neutrophil-related diseases. Hematopoietic cell-specific protein 1-associated protein X 1 (HAX1), encoded by the primary pathogenic gene of autosomal recessive severe congenital neutropenia, serves as a key target for in-depth exploration of neutrophil function. In the Hax1 myeloid knockout C57BL/6J mice and stably transduced HL-60 cells with HAX1 knockdown that we constructed, our results showed that the differentiation of granulocyte-monocyte precursor cells (GMPs) and the maturation of neutrophils were inhibited, significantly reducing the proportion of myeloid cells and neutrophils in both bone marrow and peripheral blood. In addition, HAX1 deletion disrupted mitochondrial structure and mitochondrial membrane potential in neutrophils and increased the protein levels of B-cell lymphoma 2 (BCL-2) family members and cleaved Caspase-9. Through RNA sequencing and mRNA validation, we further demonstrated that HAX1 regulates neutrophil apoptosis and maturation via the mitochondrial-mediated classical apoptotic pathway and toll-like receptor 2 (TLR2)-mediated purine-rich box 1 (PU.1) signaling. This study elucidated the critical role of HAX1 in neutrophil differentiation, maturation, and apoptosis, providing new targets for research into neutrophil-related diseases.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"349"},"PeriodicalIF":8.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683632","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":"NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment.","authors":"Beatrice Ghezzi, Irene Fiorilla, Ágata Carreira, Francesco Recco, Leonardo Sorci, Lidia Avalle, Alessia Ponzano, Francesca Mazzola, Alberto Maria Todesco, Nicoletta Tommasi, Massimiliano Gasparrini, Vito Giuseppe D'Agostino, Flavio Mignone, Alessandro Provenzani, Valentina Audrito","doi":"10.1186/s12964-025-02361-2","DOIUrl":"10.1186/s12964-025-02361-2","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"348"},"PeriodicalIF":8.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683633","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":"MIR4726^EccDNA drives bortezomib resistance in multiple myeloma by enhancing MIR4726-5p/NXF1/NKIRAS2 axis dependent autophagy.","authors":"Fangfang Li, Xinyi Long, Sishi Tang, Jinhua Yan, Jing Liu, Yunfeng Fu","doi":"10.1186/s12964-025-02340-7","DOIUrl":"10.1186/s12964-025-02340-7","url":null,"abstract":"<p><strong>Background: </strong>Despite many new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy, and drug resistance is a long-standing topic in this field. Characterized by efficient transcription without being limited by the double helix structure and promoter, extrachromosomal circular DNA (EccDNA) has been proven to be widely involved in cancer development and drug resistance.</p><p><strong>Methods: </strong>We performed circle-seq and mRNA-seq on samples from three MM patients at the time of complete response and relapse to screen EccDNA candidate molecules. Outward PCR and Sanger sequencing were used to identify EccDNA molecules. RT‒qPCR and WB were performed to detect gene expression levels. Fluorescence in situ hybridization (FISH) was carried out to detect the deletion of chromosome 17p (del (17p)). Transmission electron microscopy (TEM) was conducted to observe autophagosomes. Luciferase reporter assays were performed to validate the binding of microRNAs to target genes. Cell viability assays and apoptosis assays were employed to assess drug resistance. Xenograft tumor mouse models were established for in vivo experiments. Immunohistochemistry (IHC) was used to detect protein expression levels.</p><p><strong>Results: </strong>We successfully identified an EccDNA molecule (EccDNA^{chr17:38719676-38719812}) in one relapsed MM patient with del(17p) and named it MIR4726^EccDNA. We demonstrated that the overexpression of MIR4726^EccDNA in MM cells can increase bortezomib resistance. We further confirmed that the precursor miRNA carried by MIR4726^EccDNA can be efficiently transcribed in MM cells and that MIR4726^EccDNA drives bortezomib resistance via the MIR4726-5p/NXF1/NKIRAS2 axis. We further revealed that downregulation of NFKB inhibitor interacting Ras like 2 (NKIRAS2) activated the NF-κB pathway and increased autophagy. Moreover, we established a xenograft model of human MM via subcutaneous inoculation. We administered intra-tumoral injection of AgoMIR4726-5p and intraperitoneal injection of bortezomib and found that AgoMIR4726-5p promoted tumor progression and partially drove bortezomib resistance.</p><p><strong>Conclusions: </strong>In summary, our findings indicate that artificially synthesized MIR4726^EccDNA is functional in cells and that MIR4726^EccDNA enhances tumor progression and partially mediates drug resistance by enhancing MIR4726-5p/NXF1/NKIRAS2 axis dependent autophagy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"346"},"PeriodicalIF":8.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668979","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 gut-heart axis: a correlation between Paneth cells' dysfunction, microbiome dysbiosis, and cardiovascular diseases.","authors":"Aysa Rezabakhsh, Solomon Habtemariam, Rezayat Parvizi, Anne Meddahi-Pellé, Violeta Rodriguez Ruiz, Graciela Pavon-Djavid, Abolfazl Barzgari","doi":"10.1186/s12964-025-02335-4","DOIUrl":"10.1186/s12964-025-02335-4","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"347"},"PeriodicalIF":8.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668980","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":"Dexamethasone induces transgenerational inheritance of fetal-derived glomerulosclerosis phenotype in offspring through GR/DNMT3a mediated alterations of the lncRNA-Meg3/Notch signaling pathway.","authors":"Xiaoqi Zhao, Zhaojun Wang, Zhiping Xia, Haiyun Chen, Yanan Zhu, Songdi Wang, Yan Bao, Yutang Liu, Hui Wang, Ying Ao","doi":"10.1186/s12964-025-02346-1","DOIUrl":"10.1186/s12964-025-02346-1","url":null,"abstract":"<p><p>Prenatal dexamethasone exposure (PDE) has been reported to be associated with negative pregnancy outcomes and increased susceptibility to chronic diseases in their offspring. This study aimed to explore the transgenerational effects and mechanisms of renal developmental toxicity in offspring induced by PDE. We found that PDE caused fetal renal dysplasia and adult glomerulosclerosis phenotype in F1-F3 female offspring. Sequencing and experimental assays revealed that PDE reduced DNA methylation levels in the promoter region of the imprinted gene lncRNA Meg3 (Meg3), increased the expression of Meg3 and reduced the expression of the downstream Notch signaling pathway in kidneys of F1-F3 female fetuses. Meanwhile, Meg3 expression was increased in oocytes of PDE F1 and F2 offspring. The results of the in vitro experiments confirmed that dexamethasone activates GR and reduces DNMT3a expression in primary metanephric mesenchymal stem cells (MMSCs), which causes Meg3 hypomethylation/hyperexpression and the inhibition of the Notch signaling pathway, resulting in fetal renal dysplasia. Knockdown of GR expression, overexpression of DNMT3a, or silencing of Meg3 could reverse the downstream-associated alterations. In summary, PDE induced fetal-derived glomerulosclerosis phenotype mediated by the GR/DNMT3a/Meg3/Notch signal pathway in fetal rats, which had transgenerational inheritance effects and may be associated with increased Meg3 expression transmitted via oocytes. This study confirmed the transgenerational inheritance of fetal-derived glomerulosclerosis phenotype induced by PDE and provided an experimental basis for investigating the underlying mechanisms.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"345"},"PeriodicalIF":8.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661038","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":"Targeting androgen receptor stability and degradation: approaches for developing a therapy for spinal and bulbar muscular atrophy.","authors":"Riccardo Cristofani, Barbara Tedesco, Veronica Ferrari, Marta Chierichetti, Marta Cozzi, Paola Pramaggiore, Laura Cornaggia, Ali Mohamed, Elena Casarotto, Maria Brodnanova, Rocio Magdalena, Prashant Koshal, Margherita Piccolella, Valeria Crippa, Mariarita Galbiati, Angelo Poletti, Paola Rusmini","doi":"10.1186/s12964-025-02351-4","DOIUrl":"10.1186/s12964-025-02351-4","url":null,"abstract":"<p><p>Conformational changes of proteins can occur due to mutations or stress conditions, altering their functionality through loss of physiological or gain of pathological function. A Protein Quality Control (PQC) system exists in cells to deal with the accumulation of misfolded proteins and aggregates, comprising a network of chaperones and degradative pathways to refold or remove the aberrant proteins. Protein misfolding and PQC system impairment lead to a broad range of diseases, including neurodegenerative and neuromuscular disorders, among them spinal and bulbar muscular atrophy (SBMA). SBMA is a neuromuscular disorder caused by a polyglutamine expansion (polyQ) in the androgen receptor (AR) protein. Expanded AR (ARexp) is highly prone to misfolding and aggregation, leading to its accumulation in affected tissues. Here, we summarise the dynamics that control AR protein stability and its degradation in physiological conditions. Next, we recapitulate the current knowledge of the molecular mechanisms of SBMA pathogenesis involving the PQC system. Finally, we provide an overview of promising approaches to SBMA intervention involving the modulation of PQC system functions to reduce ARexp accumulation and its toxic effects in affected cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"344"},"PeriodicalIF":8.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661039","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":"Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation.","authors":"Man Yee Cheung, Chunmei Jiang, Imtiaz Ul Hassan, Hui Wang, Donghao Guo, Daniel Wuyang Dio, Huan Yan, Jianmin Sun, Xufeng Qi, Dongqing Cai, Wei Ge, Sheue-Yann Cheng, Wai-Yee Chan, Hui Zhao","doi":"10.1186/s12964-025-02350-5","DOIUrl":"10.1186/s12964-025-02350-5","url":null,"abstract":"<p><strong>Background: </strong>Thyroid hormone (TH) signaling drives cardiomyocyte (CM) maturation in endothermic animals. Elevated TH levels, coupled with increased basal metabolism, promote CM cell cycle exit and polyploidization, thus limiting heart regenerative potential. However, a comprehensive understanding of TH and its receptors, thyroid hormone receptors (TRs), orchestrating with other regulatory processes for heart regeneration, such as the hypoxia signaling pathway and post-injury metabolic switches, remains elusive.</p><p><strong>Results: </strong>Here, we investigated the molecular mechanisms of TH signaling in heart regeneration using a time-course sequencing experiment. We assessed heart regeneration capacity in thyroid hormone receptor alpha a (thraa) mutant zebrafish, which carry an 8-bp insertion that leads to truncation of the Thraa protein and impaired TH signaling. The thraa + 8 bp mutant zebrafish exhibited an enhanced heart regenerative response. Our study showed that, in thraa^+/- mutants, a transiently augmented inflammatory response and an extended CM proliferative window are associated with metabolic switches across different phases. Moreover, we found that thraa transcriptionally regulates hypoxia-inducible factor 3 subunit alpha (hif3a), and its knockout in zebrafish impairs heart regeneration.</p><p><strong>Conclusions: </strong>In conclusion, our study highlights the role of TH signaling via thraa in modulating zebrafish heart regeneration through metabolic regulation, inflammation, cardiac tissue regeneration, and its interplay with hif3a.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"340"},"PeriodicalIF":8.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651300","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":"Strengthening monocarboxylate transporters by adiponectin receptor agonist ameliorates diabetic peripheral neuropathy.","authors":"Tae Woo Kim, Sae-Jong Oum, Ji Hee Lim, Yaeni Kim, Eun Nim Kim, Yongjie Jin, Yu Ah Hong, Seung Yun Chae, Bum Soon Choi, Hye Won Kim, Cheol Whee Park","doi":"10.1186/s12964-025-02326-5","DOIUrl":"10.1186/s12964-025-02326-5","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"342"},"PeriodicalIF":8.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651302","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}