Cell Communication and Signaling最新文献

{"title":"PDPN⁺LTBP1⁺ cancer-associated fibroblasts induce a liver pre-metastatic niche in gastric cancer via PDPN/YAP/LTBP1 and CCL11/CCR3 axis.","authors":"Zhenxiong Zhao, Si Xiong, Ergang Guo, Hua Huang, Yu Zhang","doi":"10.1186/s12964-025-02379-6","DOIUrl":"10.1186/s12964-025-02379-6","url":null,"abstract":"<p><p>As a key component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) exhibit substantial heterogeneity and contribute significantly to tumor growth and progression. However, their involvement in shaping the pre-metastatic niche remains insufficiently characterized. This study demonstrates that extracellular vesicles (EVs) regulated by YAP signaling in podoplanin (PDPN)⁺LTBP1⁺ CAFs activate hepatic stellate cells (HSCs), thereby enhancing gastric cancer (GC) cell colonization in the liver. Mass spectrometry profiling of EVs from PDPN⁺ and PDPN⁻ CAFs identified latent transforming growth factor beta-binding protein 1 (LTBP1) as a key mediator driving the phenotypic conversion of HSCs into CAF-educated HSCs (CEHs). Exposure to LTBP1-deficient EVs resulted in attenuated CEH-induced malignancy in HGC27 and AGS GC cells. Integrated RNA sequencing and cytokine array analyses further revealed that LTBP1-containing EVs activated TGF-β signaling in HSCs, leading to CCL11 secretion. This chemokine, in turn, recruited CCR3⁺ metastatic cells to the liver microenvironment. Using a GC liver metastasis model in combination with PET-CT imaging, inhibition of the CCL11/CCR3 axis was shown to suppress CEH-driven tumor growth and metastatic potential. These findings identify LTBP1-enriched EVs from PDPN⁺LTBP1⁺ CAFs as a viable therapeutic target to impede GC liver metastasis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"402"},"PeriodicalIF":8.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201953","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":"Unraveling the molecular-pathological characteristics and cellular complexity of the tumor immune microenvironment in metastatic non-small cell lung cancer.","authors":"Shiv Bharadwaj, Joanna Maria Mierzwicka, Lucie Vaňková, Petr Malý","doi":"10.1186/s12964-025-02410-w","DOIUrl":"10.1186/s12964-025-02410-w","url":null,"abstract":"<p><p>Metastatic non-small cell lung cancer (mNSCLC) cells carry heterogeneity, not only among different subtypes but also within a single tumor. Most evidence suggests that mNSCLC exploits specific molecular drivers and mechanisms to maintain physiology, metabolism, and immune evasion during tumorigenesis. Genome-wide association studies also revealed particular mutations in the oncogenic drivers supporting tumor cell proliferation and survival, resulting in aggressive and drug-resistant phenotypes of mNSCLC. While significant progress has been made in understanding mNSCLC at the genetic and molecular levels, a considerable gap remains in understanding the dynamic interplay between intrinsic factors-particularly key tumor-associated cells-and tumor immune microenvironment (TIME) during metastasis. Hence, this review highlights histological and genetic characteristics, emphasizes the clinical relevance of metastasis, and the roles of tumor-associated cells in shaping the immunosuppressive tumor microenvironment (TME) in mNSCLC. Understanding these intricate features and mechanisms is crucial for identifying novel therapeutic targets and improving strategies to combat mNSCLC progression in diagnosed patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"400"},"PeriodicalIF":8.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193066","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":"Glioma drug development benefits from emerging phase 0 and window-of-opportunity trial paradigm.","authors":"Shenzhong Jiang, Chunlong Zhong","doi":"10.1186/s12964-025-02408-4","DOIUrl":"10.1186/s12964-025-02408-4","url":null,"abstract":"<p><p>Clinical drug development is fundamentally difficult for rare and difficult-to-treat solid tumors, for example, glioma. Glioblastoma (GBM), an invariably fatal primary brain tumor, poses a significant challenge in the realm of effective treatments, necessitating an accelerated approach to innovative drug discovery. Investigators keep requiring a process toward obtaining more reliable early-stage signals related to drug activity and a process toward translating those signals into clinical benefits efficiently in late-stage drug development. Besides, these processes could increase the likelihood of benefit in late-stage settings at a lower cost and encourage more opportunities for drug development against other rare and difficult-to-treat cancers. Phase 0 and window-of-opportunity design has been advocated for glioma, aiming to identify and eliminate ineffective therapies early in the specific drug development process, thereby enhancing overall trial quality. However, challenges persist in implementing this trial design including obtaining pre-treatment samples, establishing accurate methodological platforms and biostatistical pipelines, and identifying novel biomarkers based on both clinical and multi-omics information to predict long-term drug responses. In this review, we encapsulate current evidence regarding the window-of-opportunity design in glioma, advocating for its recognition as a standard paradigm in new drug development.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"399"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151958","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":"Aberrant neuronal firing: a paracrine route to glioblastoma expansion.","authors":"Ji Yeon Lee, Bon Il Koo, Trang Huyen Le-Kim, Yoonsung Nam","doi":"10.1186/s12964-025-02404-8","DOIUrl":"10.1186/s12964-025-02404-8","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is a highly aggressive astrocytic glioma with a devastating survival rate of less than 7%. Despite treatment with surgical resection and chemoradiotherapy, a majority of GBM cases recur. The intricate tumor microenvironment and the elusive nature of its recurrence are still controversial. Herein, we explore the role of neuronal hyperstimulation in glioblastoma cell regrowth post-chemotherapy, focusing on cancer-neuron interactions.</p><p><strong>Methods: </strong>A direct electrical stimulation system, validated by COMSOL Multiphysics simulation, was used to induce stimulation of neuronal networks through the formation of an extremely low frequency (ELF) electric field, and changes by excitability were tracked. The custom-designed co-culture system, enabling the sharing of paracrine signals in an independent microenvironment cultivation of neuronal networks and glioblastoma cell, was employed to investigate the effects of neuronal excitability on glioblastoma cell.</p><p><strong>Results: </strong>Power-frequency electric fields are applied to hippocampal neuronal networks to elicit abnormal neuronal activity, evidenced by calcium influx and neurotransmitter release. While temozolomide effectively suppresses glioblastoma cell proliferation, their co-culture with stimulated neurons reignites cancer growth. Blocking glutamate release from neuron networks counter the effects of neuronal activity, highlighting the significance of paracrine signaling in glioblastoma cell proliferation and recurrence.</p><p><strong>Conclusions: </strong>Our findings illuminate a pathway through which environmental factors contribute to GBM regrowth following chemotherapy and propose a potential therapeutic target, neuron-cancer communication, to prevent GBM recurrence.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"398"},"PeriodicalIF":8.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151754","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":"Parental S-adenosylmethionine diet defines offspring immune response via histone H3K4me3 complex and Endoplasmic Reticulum UPR.","authors":"Fang Liu, Qingyao Wang, Jun Xiong, Mengqi Wang, Hanlin Zhou, Yi Xiao","doi":"10.1186/s12964-025-02386-7","DOIUrl":"10.1186/s12964-025-02386-7","url":null,"abstract":"<p><p>S-adenosylmethionine (SAM), is a ubiquitous cofactor necessary for methyltransferase reactions. Deficiency in SAM results in dysregulation of crucial methylation and cellular dysfunction. SAM promotes innate immunity via histone H3K4me3 complex, raising the question of whether SAM supplementation in the parental generation could be reprogrammed histone modifications in offspring and thereby affect the innate immunity of descendants. In this study, we fed Caenorhabditis elegans with SAM, which led to enhance innate immunity. Furthermore, this enhancement is capable of transmitting the phenotype to subsequent generations. Transcriptome sequencing and GO functional enrichment analysis revealed that SAM induced the expression of genes involved in immune responses and IRE-1-mediated endoplasmic reticulum unfolded protein response (UPR^ER), revealing those genes were required for transgenerational innate immunity enhancement. Additionally, histone H3K4me3 marked immune response genes and IRE-1-mediated UPR^ER genes and promoted their transcription response to multigenerational innate immunity enhancement effects. Our findings indicate that the endoplasmic reticulum unfolded protein response (UPR^ER) in parental somatic cells mediates the establishment of epigenetic memory, which is preserved through the histone H3K4me3 complex in the germline across generations. Surprisingly, the transgenerational epigenetic inheritance (TEI) of the immune response induced by a SAM diet occurs independently of small RNAs. These findings offer valuable insights into the mechanisms driving multigenerational innate immunity reprogramming and clarify the effects of SAM supplementation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"397"},"PeriodicalIF":8.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139483","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":"Infection and herbicide exposure implicate c-Abl kinase in α-Synuclein Ser129 phosphorylation.","authors":"Marzieh Ehsani, Zeyang Sun, Alvaro Quevedo-Olmos, Gesa Rösler, Mahdi Rasa, Anca Kliesow Remes, Nina Hedemann, Oliver J Müller, Saskia F Erttmann, David Holthaus, Thomas F Meyer","doi":"10.1186/s12964-025-02399-2","DOIUrl":"10.1186/s12964-025-02399-2","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease is a complex, multifactorial neurodegenerative disorder characterized by aggregation of α-Synuclein into Lewy bodies, with phosphorylation at serine 129 (pSer129), serving as a key regulatory site and pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In this study, we investigate the impact of representative infectious and pesticide exposures on pSer129 α-Synuclein, with a particular focus on the role of cellular kinases in mediating this process.</p><p><strong>Methods: </strong>Neuronal cells were exposed to two distinct environmental stressors: the pesticide rotenone and the well-characterized gastric bacterium Helicobacter pylori (H. pylori). Phosphorylation of Ser129 α-Synuclein and mitochondrial damage were assessed by immunofluorescence staining or Western blotting. To investigate the involvement of c-Abl, cells were treated with mechanistically distinct c-Abl inhibitors and siRNA. Levels of pSer129 α-Synuclein were quantified by Western blotting, while the activities of the upstream serine/threonine kinase were predicted by kinase profiling and validated by Western blotting. Additionally, transcriptome analyses of treated cells were performed and ingenuity pathway analysis and DESeq2 were applied to identify neurodegenerative pathways affected by the infection/treatment.</p><p><strong>Results: </strong>The functional analysis of our RNA-sequencing data revealed that both H. pylori and rotenone induce neuroinflammatory and cellular stress response pathways. Although they likely activate c-Abl through distinct upstream mediators, both triggers ultimately promote α-synuclein phosphorylation. Treatment with the c-Abl inhibitors, Ponatinib and Asciminib, effectively prevented the accumulation of pSer129 α-synuclein and reversed the associated gene expression changes induced by H. pylori or rotenone. Additionally, GSK3β has been identified as a contributor to Ser129 phosphorylation occurring downstream of activated c-Abl signaling. Notably, the vacuolating cytotoxin (VacA) produced by H. pylori appears to play a critical role in c-Abl-mediated phosphorylation of α-synuclein at Ser129.</p><p><strong>Conclusions: </strong>These findings highlight the pivotal role of c-Abl in α-Synucleinopathies and provide insights into shared mechanisms between infection and pesticide exposure, offering potential therapeutic targets for Parkinson's disease and related pathologies involving α-Synuclein modification.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"396"},"PeriodicalIF":8.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132853","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":"Transmission Electron Microscopy-based characterization of Extracellular Vesicles from plasma and serum from Parkinson´s Disease patients.","authors":"Alexander Weiss, Alex Florin Meissner, Fanni Annamária Boros, Martin Regensburger, Regina Verena Taudte, Andreu Matamoros-Angles, Philipp Arnold, Friederike Zunke","doi":"10.1186/s12964-025-02383-w","DOIUrl":"10.1186/s12964-025-02383-w","url":null,"abstract":"<p><p>Parkinson's disease is a neurodegenerative disorder with no curative treatment option and objective biomarker profile. Extracellular Vesicles (EVs) are membrane-enclosed biological nanoparticles released from all cells of the human body. In this pilot study we compare plasma- and serum-derived EVs from Parkinson's disease (PD) patients and healthy controls (HC) utilizing a precipitation-based method. Additionally, we employ an L1CAM antibody to selectively enrich for L1CAM-positive EVs from the total plasma-/serum-derived EV fractions. Successful EV enrichment was shown in western blot experiments for CD63 and for L1CAM as well as in metabolomic analysis for a HC sample. In a side-by-side quantification,. which we based on transmission electron microscopic images from negative stain samples, we identify small but significant differences between EV diameter from PD patients and HC. To streamline the quantification process, we introduce an ImageJ-based computer algorithm for (semi-)automated quantification of EVs from negative stain electron micrographs. We observe that this (semi-)automated quantification determines a smaller diameter than manual quantification. However, the difference between PD and HC group is systematic and reveals the same relative differences calculated from manually measured total plasma-derived EV particles. In this pilot study, we introduce a new workflow implemented into an ImageJ plugin enabling to determine differences in EV size within TEM images. For our data set of plasma-derived EVs from PD patients and HC, we find small, yet consistent differences. We feel that this study contributes to the search of a clinical biomarker for PD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"395"},"PeriodicalIF":8.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088386","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":"Caffeine mitigates ROS accumulation and attenuates motor neuron degeneration in the wobbler mouse model of amyotrophic lateral sclerosis.","authors":"Aimo Samuel Christian Epplen, Maximilian Rothöft, Sarah Stahlke, Carsten Theiss, Veronika Matschke","doi":"10.1186/s12964-025-02415-5","DOIUrl":"10.1186/s12964-025-02415-5","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by oxidative stress and progressive motor neuron degeneration. This study evaluates the potential neuroprotective effects of caffeine in the Wobbler mouse, an established model of ALS.</p><p><strong>Methods: </strong>Wobbler mice received caffeine supplementation (60 mg/kg/day) via drinking water, and key parameters, including muscle strength, NAD metabolism, oxidative stress, and motor neuron morphology, were assessed at critical disease stages.</p><p><strong>Results: </strong>Caffeine delayed motor performance decline, as observed in grip strength tests during the early symptomatic phase. Histological analyses revealed that significantly fewer motor neurons were lost in caffeine-treated mice at p41, despite no changes in soma morphology. Biochemical assays demonstrated that caffeine significantly reduced ROS levels and restored NAD levels to wildtype-like values, although NMNAT2 protein expression remained unaffected. The data suggest that caffeine mitigates oxidative stress through alternative pathways, potentially involving enhanced mitochondrial function and antioxidative defenses.</p><p><strong>Conclusions: </strong>These findings highlight the potential of caffeine as a protective agent for delaying motor neuron degeneration in ALS. Future studies should explore optimal dosing strategies, combinatorial treatment approaches, and the underlying molecular mechanisms, to enable translation of these findings to human ALS patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"394"},"PeriodicalIF":8.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034686","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 mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.","authors":"Shivani R Nandha, R S Patwardhan, Deepak Sharma, Santosh K Sandur, Rahul Checker","doi":"10.1186/s12964-025-02127-w","DOIUrl":"10.1186/s12964-025-02127-w","url":null,"abstract":"<p><strong>Background: </strong>Cancer cells, which rely heavily on mitochondria for their energy demands and oncometabolites, have a high mitochondrial load, often associated with an aggressive, invasive, and metastatic phenotype. Mitochondrial ROS (mtROS), which play a causal role in cancer, represent the Achilles' heel of cancer since excessive mtROS causes protein misfolding/aggregation, resulting in cell death via proteotoxic stress. Furthermore, the detailed underlying mechanism(s) of mitochondrial oxidative stress-induced cell death remain obscure.</p><p><strong>Methods: </strong>Cell growth was estimated by MTT assay, clonogenic assay, live-cell imaging and flow cytometry. Intracellular ROS, mtROS, glutathione and antioxidant levels were studied by spectrophotometry. RNAseq and Western blotting were performed to elucidate the underlying mechanism(s). In vivo efficacy was evaluated using a syngeneic mouse model.</p><p><strong>Results: </strong>We employed a mitochondria-targeted agent to disrupt the mitochondrial redox balance. Among tumors of different origins, such as lung, breast, prostate, bone, skin, cervical and liver, triple-negative breast cancer (TNBC) exhibited the highest sensitivity to mitochondrial oxidative stress. Compared with the parent compound, mitochondria-targeted agent showed 39-fold more effectiveness in killing TNBCs. We observed a possible correlation between the mitochondrial load in different cancer cell lines and their sensitivity to mitochondrial oxidative stress. Transcriptomic analysis revealed an enrichment of biological response to unfolded and/or misfolded proteins, which are regulated by two key proteases, Lon peptidase 1 (LONP1) and Caseinolytic protease P (CLPP), that control mitochondrial proteostasis. Bioinformatics analyses revealed enhanced expression and a strong positive correlation between these proteases in breast cancer patients, with highest expression observed in TNBC. Additionally, an early relapse was observed in breast cancer patients over-expressing both LONP1 and CLPP. Mitochondrial oxidative stress triggered a decrease in the native functional forms and an increase in the aggregated forms of LONP1 and CLPP, thereby disrupting mitochondrial proteostasis. Interestingly, no such changes were observed in normal cells. Mechanistically, excess mtROS induced proteotoxic stress and mitochondrial dysfunction, culminating in growth inhibition both in vitro and in vivo.</p><p><strong>Conclusion: </strong>Our studies, for the first time, show that the mitochondrial load and induction of mtROS for concomitant inhibition of LONP1 and CLPP to induce proteotoxic stress, could be novel therapeutic targets for cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"393"},"PeriodicalIF":8.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994540","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":"ATE1 promotes breast cancer progression via arginylation-dependent regulation of MAPK-MYC signaling.","authors":"Laxman Nawale, Shinyeong Ju, Jung Gi Kim, Nak Kyun Soung, Bo Yeon Kim, Cheolju Lee, Hyunjoo Cha-Molstad","doi":"10.1186/s12964-025-02376-9","DOIUrl":"10.1186/s12964-025-02376-9","url":null,"abstract":"<p><strong>Background: </strong>Arginyl-tRNA-protein transferase (ATE1) catalyzes N-terminal arginylation, a regulatory protein modification implicated in various cellular processes, including proliferation, apoptosis, and migration. Although ATE1 has context-dependent roles in cancer, its specific function in breast cancer remains unclear. This study investigates the oncogenic role of ATE1 across multiple breast cancer subtypes and its underlying molecular mechanisms.</p><p><strong>Methods: </strong>ATE1 expression in breast cancer was evaluated using TCGA data and immunoblotting across breast cancer cell lines and normal mammary epithelial cells (HMEC). Functional studies using siRNA- and shRNA-mediated knockdown assessed ATE1's role in cell viability, clonogenic growth, migration, and tumorigenesis in vitro and xenograft models. Quantitative proteomics, R-catcher-based N-terminomics, and pathway analyses were employed to identify ATE1-dependent signaling networks, with a focus on MAPK-MYC axis regulation. Flow cytometry and immunoblotting were used to assess cell cycle progression, apoptosis, and MYC stability.</p><p><strong>Results: </strong>ATE1 was significantly upregulated in breast cancer cells and associated with poor prognosis in early-stage patients. ATE1 depletion selectively impaired viability, proliferation, and migration in breast cancer cells, but not in HMECs. In vivo, ATE1 silencing suppressed tumor growth in xenograft models. Proteomic profiling revealed that ATE1 regulates the cell cycle and survival pathways in a subtype-specific manner, particularly through modulation of the MAPK-MYC-CDK6 axis in luminal T-47D cells. ATE1 stabilized MYC protein via ERK-mediated phosphorylation at Ser62, promoting cell cycle progression and suppressing apoptosis. Rescue experiments confirmed that ATE1's tumor-promoting activity depends on its arginyltransferase function.</p><p><strong>Conclusions: </strong>ATE1 promotes breast cancer progression by enhancing cell proliferation, survival, and migration through MAPK-dependent stabilization of MYC in a lineage-specific context. These findings identify ATE1 as a potential therapeutic target and highlight the relevance of protein arginylation in the molecular heterogeneity of breast cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"390"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12403503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144979480","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}