Biochimica et biophysica acta. General subjects最新文献

{"title":"Targeting PCK2 alleviates GERD by suppressing MAPK-dependent endoplasmic reticulum stress and oxidative stress-induced apoptosis.","authors":"Na Wang, Jia Zhu","doi":"10.1016/j.bbagen.2026.130996","DOIUrl":"https://doi.org/10.1016/j.bbagen.2026.130996","url":null,"abstract":"<p><p>Gastroesophageal reflux disease (GERD) is a digestive disease characterized by endoplasmic reticulum stress (ERS) imbalance and oxidative stress-induced cellular injury. However, the key ERS-related regulators involved in GERD progression remain unclear. Here, we identified PCK2 as a novel GERD-associated ERS regulator and explored its role and underlying mechanisms in GERD development. Bioinformatics analysis of the GEO dataset GSE148381 identified four overlapping ERS-related candidate genes in GERD tissues. Among these candidates, PCK2 was selected based on its consistent upregulation in ABS-treated HET-1 A cells, as confirmed by RT-qPCR and western blotting, with a 1.2-fold increase in mRNA expression and a 2.67-fold increase in protein abundance compared with control cells. Functional studies demonstrated that PCK2 silencing attenuated ERS activation by reducing ATF6, PERK, p-PERK, CHOP, and XBP1 expression. PCK2 knockdown markedly alleviated oxidative stress, reducing ROS and MDA levels by approximately 91% and 34%, respectively, decreasing apoptosis by approximately 36%, and improving cell viability, whereas PCK2 overexpression exerted opposite effects. In vivo, PCK2 knockdown alleviated esophageal injury and suppressed ERS responses. Mechanistically, Gene Set Enrichment Analysis revealed enrichment of PCK2-associated genes in the MAPK pathway, and further experiments showed that PCK2 promoted p38 MAPK activation through enhanced p38 phosphorylation. Pharmacological inhibition of p38 signaling with SB203580 abolished PCK2-induced ERS, oxidative stress, and apoptosis in HET-1 A cells. Collectively, our findings indicate that PCK2 acts as a potential therapeutic target in GERD by promoting p38 MAPK activation, thereby exacerbating ERS, oxidative stress, and apoptosis.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130996"},"PeriodicalIF":2.9,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IQSEC2 and ARF1 are involved in the development of the dentate gyrus.","authors":"Hidenori Ito, Tomoki Ishiguro, Koh-Ichi Nagata","doi":"10.1016/j.bbagen.2026.130994","DOIUrl":"10.1016/j.bbagen.2026.130994","url":null,"abstract":"<p><p>The IQ motif and SEC7 domain-containing protein 2 (IQSEC2) is a guanine nucleotide exchange factor (GEF) for ARF family small GTPases and is encoded by the IQSEC2 gene located on chromosome Xp11.22. More than 120 pathogenic variants in IQSEC2 have been identified in patients with neurodevelopmental disorders. In this study, we aimed to clarify the role of IQSEC2 during neonatal mouse dentate gyrus development using in vivo electroporation. Electroporation of a GFP expression vector together with a short hairpin RNA (shRNA) targeting IQSEC2 caused dentate granule neurons to stop at the boundary between the granule cell layer and the hilus (GCL/hilus). IQSEC2-deficient dentate granule cells exhibited increased distal dendritic complexity compared with control cells. IQSEC2 knockdown also reduced spine head diameter without affecting spine density. In contrast, exogenous IQSEC2 expression increased proximal dendritic complexity in neonatal dentate granule cells. We examined the ARF selectivity of IQSEC2 GEF activity and found that IQSEC2 activates ARF1, ARF3, and ARF6. Functional analyses revealed that ARF1 knockdown also confined dentate granule cells to the GCL/hilus region, which was consistent with the observation following IQSEC2 knockdown. In contrast, knockdown of ARF3 or ARF6 had no significant effect. Together, these results suggest that the IQSEC2 and ARF1 play a critical role in regulating neuronal positioning and dendritic development in the neonatal dentate gyrus.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130994"},"PeriodicalIF":2.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can kinetic and thermodynamic parameters of protein-ligand dissociation be extracted from AFM pulling data?","authors":"Ramesh Chandra Tripathi, Peter M Hoffmann","doi":"10.1016/j.bbagen.2026.130990","DOIUrl":"10.1016/j.bbagen.2026.130990","url":null,"abstract":"<p><p>Atomic Force Microscopy (AFM) is a promising tool to measure dissociation rates and binding distances in the single-molecule regime. However, interpretation of the obtained rupture data can be challenging. The unbinding process between two complex molecules is often characterized by a spectrum of barrier heights that cannot be parametrized by a single barrier height. In standard analysis, different barriers can be discerned only by measuring over at least 4-5 orders of magnitude of the pulling force rate, which can be difficult to achieve with AFM. Here, we used fits of the full rupture force histograms to address this complexity. We found that multiple unbinding paths can be discerned from measurements at just a few force rates using this approach. We also show how multiple rupture events - situations where multiple bonds breaking simultaneously appear as single rupture events - can be addressed in the analysis.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130990"},"PeriodicalIF":2.9,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astragaloside IV is associated with TFRC-dependent ferroptosis and JAK2/STAT3 pathway inhibition in osteosarcoma cells.","authors":"Qianqian Li, Ming Qian, Jun Tian, Jianlou Chen, Ping Guo, Wei Chen","doi":"10.1016/j.bbagen.2026.130992","DOIUrl":"10.1016/j.bbagen.2026.130992","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma is a common malignant bone tumor in children and adolescents. Conventional chemotherapy has drug resistance and side effects, and new treatments are needed. Astragaloside IV (AS-IV) has anti-tumor effects, but its mechanism in osteosarcoma is unclear.</p><p><strong>Methods: </strong>MG63/Saos2 osteosarcoma cells were divided into control, AS-IV (20/40 μM), Erastin (ferroptosis inducer), AS-IV + Lip-1 (ferroptosis inhibitor), AS-IV + short hairpin RNA negative control (shNC), and AS-IV + short hairpin RNA Transferrin Receptor 1 (shTFRC) (transfection of shTFRC lentiviral vector) groups. Cell counting kit-8, flow cytometry, immunofluorescence, kit detection, quantitative real-time polymerase chain reaction, and Western blot were used to detect cell viability, apoptosis, reactive oxygen species (ROS), iron metabolism, oxidative stress, and Janus Kinase 2/Signal Transducers and Activators of Transcription 3 (JAK2/STAT3) pathway-related indicators.</p><p><strong>Results: </strong>AS-IV could concentration-dependently inhibit the viability of MG63 and Saos2 cells, promote cell apoptosis and ROS production, upregulate the levels of Fe²⁺, labile iron pool (LIP) and malondialdehyde (MDA), downregulate the expression of Ferritin Heavy Chain 1 (FTH1) and Glutathione Peroxidase 4 (GPX4) mRNA and the activities of superoxide dismutase (SOD) and catalase (CAT), and significantly inhibit the phosphorylation of JAK2 and STAT3. Lip-1 could reverse these effects. Moreover, after TFRC knockdown, the regulatory effects of AS-IV on the viability, apoptosis, iron metabolism, oxidative stress and JAK2/STAT3 pathway of osteosarcoma cells were significantly weakened.</p><p><strong>Conclusion: </strong>AS-IV is associated with ferroptosis induction and JAK2/STAT3 pathway inhibition in osteosarcoma cells, and these effects are attenuated by TFRC knockdown, providing new targets and theoretical basis for the treatment of osteosarcoma.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130992"},"PeriodicalIF":2.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone methyltransferase inhibitors prevent lens opacity in diabetic cataract rats.","authors":"Haoran Chai, Yaoyao Guo, Rui Luo, Shi Li, Ruoyi Xie, Han Liu, Xuejun Gu, Chunyi Liu","doi":"10.1016/j.bbagen.2026.130993","DOIUrl":"10.1016/j.bbagen.2026.130993","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the effect and mechanism of histone methylation on galactose-induced lens opacity.</p><p><strong>Methods: </strong>Lenses from SD rats were cultured in 30 mM galactose medium to induce opacification, with intervention using four histone methyltransferase inhibitors (GSK126, Pinometostat, GSK3326595, BIX-01294). Lens opacity, structural changes (HE staining/transmission electron microscopy (TEM)), differentially expressed genes (high-throughput sequencing), and validated targets (qPCR) were analyzed. A diabetic cataract (DC) rat model was established via intraperitoneal galactose injection, with BIX-01294 intervention. Ocular lesions (fundus/slit-lamp examination), lens structure (HE staining), AR/TNF-α levels (ELISA), and Pikfyve mRNA expression (qPCR) were assessed. Ex vivo, YM201636 (a Pikfyve inhibitor) was used to intervene in galactose-induced opacity, with opacity observation and structural evaluation (HE staining/TEM).</p><p><strong>Results: </strong>The four histone methyltransferase inhibitors ameliorated lens opacity to varying degrees. HE staining and TEM results showed that histone methyltransferase inhibitors alleviated lens injury, with BIX-01294 exhibiting the most pronounced effect. High-throughput sequencing of the model group and the BIX-01294 intervention group revealed that after BIX-01294 treatment, 113 genes were upregulated and 60 genes were downregulated. qPCR validation showed that mRNA expression levels of Pth1r, Fam111a, Pikfyve, and H19 were significantly downregulated after BIX-01294 intervention. Furthermore, BIX-01294 intervention reduced lens injury, decreased AR activity and TNF-α content, and lowered Pikfyve mRNA expression in DC rats. Intervention with YM201636 (a Pikfyve inhibitor) alleviated galactose-induced lens opacity and improved lens damage in vitro.</p><p><strong>Conclusion: </strong>Histone methyltransferases are involved in lens opacity in DC rats by regulating Pikfyve gene expression.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130993"},"PeriodicalIF":2.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer activity of Pseudomonas fluorescens lectin (PFL) targeting high-mannose glycans on breast cancer cells","authors":"Yuichiro Sato ,&nbsp;Kohei Kawabata ,&nbsp;Chiho Murakami ,&nbsp;Yuta Hatori ,&nbsp;Takanori Kubo ,&nbsp;Yuya Ohtsuki ,&nbsp;Hiroyuki Nishi ,&nbsp;Akira Tokumura ,&nbsp;Kinjiro Morimoto","doi":"10.1016/j.bbagen.2026.130914","DOIUrl":"10.1016/j.bbagen.2026.130914","url":null,"abstract":"<div><div>Aberrant glycosylation is one of the key characteristics of cancer cells. High-mannose-type N-glycans are highly expressed in various types of cancer, making them potentially important therapeutic targets. As a basis for developing new therapeutic drugs targeting high-mannose glycans, we employed <em>Pseudomonas fluorescens</em> lectin (PFL) that specifically binds to high-mannose glycans as a model compound, and analyzed the cellular responses of MDA-MB-231 and T47D breast cancer cell lines. In both cell types, PFL induced the internalization and degradation of cancer-associated molecules such as epidermal growth factor receptor (EGFR), integrins, and immune checkpoint ligands via autophagy, ultimately leading to apoptotic cell death. In T47D cells, changes were observed in the cellular distribution and expression levels of hormone receptors and human epidermal growth factor receptor 2 (HER2) upon treatment with PFL, suggesting a possible compensatory response. Comprehensive analysis of cellular lipids revealed that lysophospholipids were dramatically increased by PFL treatment, regardless of breast cancer cell type. These changes may reflect the dynamic reorganization of lipid membranes associated with membrane traffic and autophagy. Time-lapse experiments using a redox sensor designed to localize to the cell membrane showed that cells transitioned to an oxidized state following PFL treatment. Furthermore, inflammatory substances such as interleukin 8 (IL-8) were significantly increased in MDA-MB-231 cells but not in T47D cells. The results provide insight into the responses and resistance of breast cancer cells to glycan-targeted therapies.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 5","pages":"Article 130914"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-dose ascorbic acid prolongs the suppression of cell proliferation by enhancing intracellular oxidative stress–induced damage and inhibits invasion and adhesion in human fibrosarcoma HT-1080 cells","authors":"Yasukazu Saitoh ,&nbsp;Yusuke Tanimura ,&nbsp;Shun Ueda ,&nbsp;Tomoya Furuhata ,&nbsp;Manato Takeda ,&nbsp;Kouichi Okawachi ,&nbsp;Yusuke Fukukita","doi":"10.1016/j.bbagen.2026.130908","DOIUrl":"10.1016/j.bbagen.2026.130908","url":null,"abstract":"<div><div>Pharmacological vitamin C (VC) infusion therapy has shown efficacy against various cancer types; however, there are few reports on its effects on fibrosarcoma. This study investigated the impact of high-dose ascorbic acid (AsA), the reduced form of VC, on human fibrosarcoma HT-1080 cells. High-dose AsA (2–5 mM) markedly decreased HT-1080 cell viability compared with normal fibroblasts, indicating cancer cell selectivity. In contrast, dehydroascorbic acid (DehAsA), the oxidized form of AsA, exhibited no cytotoxicity toward cancer cells. Studies using D-AsA and AsA transport inhibitors demonstrated that intracellular AsA transport was not required for cytotoxicity in HT-1080 cells. Our results showed that high-dose AsA induced extracellular H₂O₂ production and increased intracellular H₂O₂, reactive oxygen species (ROS), and Fe²⁺ levels in HT-1080 cells compared with normal fibroblasts, suggesting that strong oxidative stress triggers actin disruption, ATP depletion, DNA damage, and reduced DNA synthesis. Additionally, a 1-h AsA exposure produced a sustained inhibitory effect on cell proliferation lasting at least 72 h. Moreover, high-dose AsA inhibited HT-1080 cell invasion and adhesion, with increased intracellular ROS likely contributing to these effects. These results indicate that high-dose AsA generates extracellular H₂O₂ and subsequently induces cancer cell-specific oxidative damage due to differences in intracellular H₂O₂ and Fe²⁺ levels, which differ between normal fibroblasts and HT-1080 cells. These actions lead to cancer cell-selective toxicity and prolonged growth-suppressive effects induced by high-dose AsA.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130908"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COX-2 downregulation via G-quadruplex structure induction in the PTGS2-promoter region by mononuclear octahedral cobalt(III) Schiff base complex [CoL3] in colorectal cancer cells","authors":"Abdolvahab Moshtaghian ,&nbsp;Abasalt Hosseinzadeh Colagar ,&nbsp;Ali Khaleghian ,&nbsp;Tahereh Zahedi","doi":"10.1016/j.bbagen.2026.130909","DOIUrl":"10.1016/j.bbagen.2026.130909","url":null,"abstract":"<div><div>G-quadruplex structures within the promoter regions of some oncogenes diminish transcriptional activity. The suppression and downregulation of Cyclooxygenase-2 (COX-2), which is encoded by the prostaglandin-endoperoxide synthase 2 (<em>PTGS2</em>) gene, could control the size of colorectal cancer tumors. This study aimed to investigate the impact of a mononuclear octahedral cobalt(III) Schiff base complex [CoL₃] (L = 2-((allylimino)methyl)-6-methoxyphenol) on the G-quadruplex structures in the <em>PTGS2</em> promoter region and to assess its downregulation effects in the human colorectal cancer cell line HT-29. At first, molecular docking was used to evaluate the binding of [CoL₃] to the <em>PTGS</em>2 promoter region. Then, the potential and stabilization of G-quadruplex formation in the PTGS2 promoter motifs were investigated using circular dichroism (CD) spectroscopy, polyacrylamide gel electrophoresis, and polymerase chain reaction (PCR) stop assays. COX-2 expression was also assessed by real-time PCR and western blot. Molecular docking analysis indicates that [CoL₃] has a potent interaction with the <em>PTGS2</em> promoter region. Additionally, [CoL₃] has an intense inhibitory effect on the <em>PTGS2</em>-PCR stop assay. The CD measurements confirmed the conformational property of G-quadruplex DNA structures induced by [CoL₃]. Treatment of colorectal cancer cells with the [CoL₃] resulted in a modest increase in <em>PTGS2</em> expression by a mean factor of 1.69 (<em>p</em> &lt; 0.05). Conversely, the expression of COX-2 proteins was downregulated significantly, with a mean protein intensity of 0.47 (<em>p</em> &lt; 0.001). Therefore, [CoL₃] induces G-quadruplex formation in the promoter region of <em>PTGS2</em>, which ultimately inhibits protein expression of COX-2. This means that [CoL₃] can be an effective agent for colorectal cancer treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130909"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendrimer-based therapeutics in neurological disorders: Innovations and clinical prospects","authors":"Karthikeya Lalitha Siddhartha Pallem,&nbsp;Anjali Jain,&nbsp;Anurag Aswal,&nbsp;Smita Jain,&nbsp;Umesh Gupta","doi":"10.1016/j.bbagen.2026.130903","DOIUrl":"10.1016/j.bbagen.2026.130903","url":null,"abstract":"<div><div>The incidence of brain tumors and other neurodegenerative diseases has been increasing, whereas the treatment opportunities are limited. Brain delivery of the therapeutics has been restricted because of the presence of blood-brain barrier (BBB). Only molecules of molecular weight &lt;400 Da and lipid-soluble are able to cross the BBB making it hard for the treatment. This demands the development of effective nano-carriers that can penetrate the BBB and deliver the therapeutics more efficiently and site specifically. Dendrimers are highly branched polymers having unique structural and functional properties, emerging as the promising carriers for delivering chemotherapy and gene therapy to the central nervous system (CNS). This review comprehensively explores the development of dendrimers, mechanisms in delivering therapeutic agents to the brain across the blood-brain barrier (BBB) and the progress over past years in utilizing the dendrimers for brain delivery of therapeutics.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130903"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous expression of the laminin-binding O-mannosyl glycan on α-dystroglycan in pancreatic cancer cell line MIA PaCa-2 and the correlation with cell properties","authors":"Rieko Imae ,&nbsp;Yuuki Shichi ,&nbsp;Satoshi Ninagawa ,&nbsp;Toshiyuki Ishiwata ,&nbsp;Hiroshi Manya","doi":"10.1016/j.bbagen.2026.130907","DOIUrl":"10.1016/j.bbagen.2026.130907","url":null,"abstract":"<div><div>α-Dystroglycan (α-DG) is a central component of the dystrophin-glycoprotein complex, with the characteristic O-mannosyl glycan modification, which binds to several extracellular matrix proteins such as laminin. Disruption in the synthesis of laminin-binding glycan on α-DG is related to muscular dystrophies. In addition, loss of this glycan is frequently observed in many cancers, including pancreatic ductal adenocarcinoma (PDAC), correlating with poor prognosis. However, the significance of this glycan in the pathology of cancer remains unclear. This study aimed to clarify the biological significance of laminin-binding O-mannosyl glycan on α-DG in PDAC cells. Since a tumor-derived cancer cell line consists of cells with diverse characteristics, we first obtained several single-cell-derived clones using MIA PaCa-2, a commonly used undifferentiated PDAC cell line, and found that the laminin-binding glycan modification level on α-DG differs among the various clones. The glycan modification level correlated well with the mRNA expression level of LARGE1, the enzyme that synthesizes the laminin-binding structure on the glycan. We analyzed several PDAC cell properties, such as cellular morphology, proliferation and migration/invasion abilities, and examined their correlation with the glycan modification. We found that a high level of laminin-binding O-mannosyl glycan modification on α-DG correlated with the elongated cell morphology, high invasion ability, and low membrane blebbing activity, and vice versa. Furthermore, manipulation of the laminin-binding O-mannosyl glycan synthesis confirmed that this glycan partially contributed to these properties. Overall, this study provides valuable insights into the roles of the laminin-binding glycan on α-DG in PDAC.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 4","pages":"Article 130907"},"PeriodicalIF":2.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}