Cellular signalling最新文献

{"title":"Regulation of diabetic disc degeneration: The role of AGEAT/miR-204-5p/Mapk4 axis in nucleus pulposus cells' mitochondrial function and apoptosis","authors":"Zhiguang Zhang ,&nbsp;Ouqiang Wu ,&nbsp;Jiahao Ying ,&nbsp;Yuxin Jin ,&nbsp;Hui Wang ,&nbsp;Haijun Tian ,&nbsp;Qizhu Chen ,&nbsp;Linjie Chen ,&nbsp;Chen Tao ,&nbsp;Chao Lou ,&nbsp;Morgan Jones ,&nbsp;Xiangyang Wang ,&nbsp;Pooyan Makvandi ,&nbsp;Shuying Shen ,&nbsp;Bin Li ,&nbsp;Aimin Wu","doi":"10.1016/j.cellsig.2025.111857","DOIUrl":"10.1016/j.cellsig.2025.111857","url":null,"abstract":"<div><div>Chronic low back pain associated with intervertebral disc degeneration (IVDD) is significantly aggravated in patients with diabetes mellitus (DM); however, the underlying molecular mechanisms remain unclear. This study explored the role of the long non-coding RNA AGEAT (AGE-associated transcript) in the pathogenesis of DM-associated IVDD. Whole-transcriptome sequencing of rat nucleus pulposus cells (NPCs) treated with advanced glycation end products (AGEs) revealed a time-dependent upregulation of AGEAT. AGEAT overexpression induced NPC apoptosis, mitochondrial dysfunction, and extracellular matrix (ECM) degradation. Mechanistically, RNA fluorescence in situ hybridization localized AGEAT to the cytoplasm, where it acted as a competing endogenous RNA (ceRNA) by directly binding miR-204-5p, thereby relieving repression of its target Mapk4. Silencing AGEAT via siRNA significantly reduced apoptosis, restored mitochondrial function, and preserved ECM integrity. In vivo, intra-discal injection of AAV-sh-AGEAT in diabetic IVDD rats significantly improved disc integrity, as evidenced by a reduction in MRI Pfirrmann grade and histological preservation of NPC density and collagen II content. Collectively, these findings establish AGEAT as a key ceRNA that exacerbates diabetic IVDD via the miR-204-5p/Mapk4 axis, promoting NPC apoptosis, mitochondrial dysfunction, and ECM degradation. Targeting this pathway—through AGEAT silencing or miR-204-5p activation—represents a promising therapeutic strategy for mitigating diabetes-associated disc degeneration. This study reveals the critical role of the AGEAT/miR-204-5p/Mapk4 axis in the progression of DM-associated IVDD, suggesting a potential therapeutic strategy for its treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111857"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090105","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":"METTL14 promotes TBK1 mRNA stability through IGF2BP3-recognized m6A modification and enhances mitophagy in BMSCs","authors":"Yue Shen ,&nbsp;Long Wang ,&nbsp;Zixiang Guo ,&nbsp;Jiaohong Wang ,&nbsp;Runzi Zhang ,&nbsp;Chunbo Tang ,&nbsp;Jin Wu","doi":"10.1016/j.cellsig.2025.111873","DOIUrl":"10.1016/j.cellsig.2025.111873","url":null,"abstract":"<div><div>Osteoporosis, particularly postmenopausal osteoporosis, represents a growing global health challenge characterized by impaired bone remodeling and increased fracture risk. The impairment of bone regeneration manifests in the field of oral and maxillofacial medicine as delayed alveolar bone healing after tooth extraction and poor osseointegration of dental implants, significantly compromising oral functional rehabilitation. This study investigates the role of METTL14 in osteogenic differentiation and its potential regulatory mechanisms in bone metabolism. We identified differential expression patterns of METTL14 in bone marrow-derived mesenchymal stem cells (BMSCs) between osteoporotic patients and healthy controls. Through loss-of-function experiments, we further demonstrated the critical role of METTL14 in promoting osteogenic differentiation, providing direct evidence for its functional importance in bone metabolism regulation. Transcriptome sequencing analysis revealed a significant association between METTL14 and mitophagy. JC-1 assay, Mitosox assay, mt-Keima assay, western blotting and immunofluorescence demonstrated METTL14's positive regulatory role in mitophagy, with TBK1 identified as the most significantly altered downstream target through qRT-PCR and rescue experiments. We further elucidated that IGF2BP3, an m6A reader, promotes osteogenesis and regulates TBK1 mRNA stability, as evidenced by Actinomycin D treatment and mitochondrial-lysosomal colocalization assays. In vivo experiments showed that METTL14 overexpression enhanced alveolar bone healing in ovariectomized osteoporotic mice. These findings provide novel evidence supporting METTL14 as a potential therapeutic target for osteoporosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111873"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093088","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":"Characterization of functionally relevant G protein-coupled receptors in endometriotic epithelial cells","authors":"Matteo Prisinzano ,&nbsp;Isabelle Seidita ,&nbsp;Paola Bruni ,&nbsp;Felice Petraglia ,&nbsp;Caterina Bernacchioni ,&nbsp;Dagmar Meyer zu Heringdorf ,&nbsp;Chiara Donati","doi":"10.1016/j.cellsig.2025.111876","DOIUrl":"10.1016/j.cellsig.2025.111876","url":null,"abstract":"<div><div>Endometriosis is a chronic inflammatory disease characterized by the invasion of endometrial cells outside the uterine cavity. Current treatments for the disease, whose typical symptoms are pain and infertility, are unsatisfactory, relying on the surgical removal of the lesions and hormonal therapies with high symptom relapse and collateral effects, respectively. The aim of the present study was to exploit the rationale for G protein-coupled receptors (GPCRs) as non-hormonal therapeutic targets for this disease. To this end, human endometriotic epithelial cells 12Z were employed to characterize GPCR-mediated increases in intracellular Ca²⁺ concentrations ([Ca²⁺]_i) using fluo-4, and cell invasion was measured using Boyden chamber assays. The results showed that the GPCR ligands oxytocin, bradykinin, histamine, lysophosphatidic acid, and sphingosine 1-phosphate (S1P) efficiently increased [Ca²⁺]_i and induced cell invasion in endometriotic cells. In contrast, neuropeptide S, previously identified as a pro-invasive mediator, did not increase [Ca²⁺]_i in 12Z cells. Notably, pretreatment with pertussis toxin significantly reduced S1P-dependent [Ca²⁺]_i increase and cell invasion, highlighting the involvement of G_i-mediated signaling. Employing specific agonists and/or antagonists of S1P receptor isoforms, we demonstrated that S1P₁/S1P₃/S1P₅, but not S1P₂/S1P₄ mediated the [Ca²⁺]_i increases in this cellular model. Moreover, activation of S1P₁/S1P₄/S1P₅, but not S1P₂/S1P₃, efficiently stimulated cell invasion.</div><div>Taken together, we identified several GPCRs that are functionally relevant in human endometriotic epithelial cells and may potentially serve as targets for non-hormonal therapy of endometriosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111876"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090104","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":"IGFBP7: A novel biomarker involved in a positive feedback loop with TGF-β1 in idiopathic pulmonary fibrosis","authors":"Tao Zhu ,&nbsp;Ben-Rong Mu ,&nbsp;Bin Li ,&nbsp;Zhao Ran ,&nbsp;Dong-Mei Wang ,&nbsp;Ya Zhou ,&nbsp;Li Liu ,&nbsp;Qing-Lin Wu ,&nbsp;Mei-Hong Lu ,&nbsp;Da-Qian Xiong","doi":"10.1016/j.cellsig.2025.111867","DOIUrl":"10.1016/j.cellsig.2025.111867","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible scarring of the lungs, predominantly affecting older adults. The limited therapeutic options available are largely due to an insufficient understanding of IPF etiology and pathogenesis. This study investigated potential biomarkers to enhance IPF diagnosis and treatment strategies. Through single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing analyses of public datasets, four hub genes—FTH1, FABP5, DCXR, and IGFBP7—were identified as strongly associated with IPF. Subsequent validation in in vivo and in vitro models confirmed IGFBP7 as a novel biomarker. Double immunofluorescence staining and scRNA-seq analysis revealed that IGFBP7 expression is elevated in IPF epithelial cells. IGFBP7 shows potential for early diagnosis of IPF and can differentiate IPF from other diseases. Gene set enrichment analysis revealed the involvement of IGFBP7 in IPF pathogenesis, particularly through its strong connection to the TGF-β signaling pathway, which drives inflammation and fibrosis. In vitro studies with the TGF-β inhibitor SB431542 showed that inhibition of the TGF-β pathway significantly reduced IGFBP7 expression. Furthermore, IGFBP7 knockdown decreased the expression of markers associated with epithelial-mesenchymal transition and fibrosis while suppressing TGF-β1 expression. These results suggest that IGFBP7 forms a positive feedback loop with TGF-β1. In conclusion, this research identified IGFBP7 as a promising biomarker with significant diagnostic and therapeutic potential for IPF. These insights pave the way for improved diagnostics and the development of targeted antifibrosis therapies, while deepening our understanding of IPF mechanisms.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111867"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090103","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":"Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells","authors":"Tingyu Chen,&nbsp;Yiming Xu,&nbsp;Fan Yang,&nbsp;Yanxin Pan,&nbsp;Ning Ji,&nbsp;Jing Li,&nbsp;Xin Zeng,&nbsp;Qianming Chen,&nbsp;Lu Jiang,&nbsp;Ying-Qiang Shen","doi":"10.1016/j.cellsig.2025.111874","DOIUrl":"10.1016/j.cellsig.2025.111874","url":null,"abstract":"<div><div>Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators—c-Myc, mTORC, KRAS, p53, and HIF—in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111874"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072368","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":"SOX12 promotes serine synthesis and tumor progression in endometrial cancer","authors":"Zi-hui Zhang ,&nbsp;Yan Hui ,&nbsp;Qiong Wan ,&nbsp;Xing-yan Hu ,&nbsp;Hao Wang ,&nbsp;Cheng-cheng Liu ,&nbsp;Feng-zhi Wan ,&nbsp;Chun-yan Huang ,&nbsp;Feng-xian Yi ,&nbsp;Shu-hua Zeng ,&nbsp;Shuang Li ,&nbsp;Hong Ye","doi":"10.1016/j.cellsig.2025.111870","DOIUrl":"10.1016/j.cellsig.2025.111870","url":null,"abstract":"<div><div>Studies have demonstrated that the sex-determining region Y-box 12 (SOX12), a key oncogene, is highly expressed in various tumors and is associated with poor prognosis. Unfortunately, the effect of SOX12 in endometrial cancer (EC) remains unclear. Here, we discovered that SOX12 expression was significantly elevated in EC tissues from advanced-stage patients and patients who died. Additionally, high expression of SOX12 was shown to predict poor overall survival (OS) and recurrence-free survival (RFS), indicating that SOX12 is an independent prognostic factor for patients with EC. Furthermore, the overexpression or knockdown of SOX12 significantly enhanced or inhibited the activity, proliferation, migration, invasion ability, serine synthesis pathway (SSP) activity and metabolism, respectively, of EC cells. Moreover, overexpression of SOX12 significantly promoted the growth and malignant progression of subcutaneously transplanted tumors, facilitated the formation of lung metastatic nodules, and ultimately reduced the survival time of nude mice. In contrast, stable suppression of SOX12 markedly inhibited the growth of subcutaneous grafts and the formation of lung metastatic nodules in introduced <em>via</em> the tail vein, while also increasing the survival time of nude mice. Mechanistically, SOX12 directly binds to the promoter of the target gene 3-phosphoglycerate dehydrogenase (PHGDH), activating its transcription and enhancing the SSP and metabolism, which ultimately contributes to the malignant progression of EC. Surprisingly, we found that the combination of serine deprivation and SOX12 knockdown had a more pronounced effect on inhibiting the malignant progression of EC <em>in vivo</em> and <em>in vitro</em>. In summary, our study not only enhances the understanding of the carcinogenic mechanisms associated with SOX12 but also presents a potential strategy for molecularly targeted therapy in EC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111870"},"PeriodicalIF":4.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085979","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":"Role of ferroptosis in breast cancer: Molecular mechanisms and therapeutic interventions","authors":"Bo Wang ,&nbsp;Zi-Hui Liu ,&nbsp;Jun-Jie Li ,&nbsp;Jia-Xing Xu ,&nbsp;Ya-Mei Guo ,&nbsp;Jing-Xue Zhang ,&nbsp;Ti Chu ,&nbsp;Zhi-Fen Feng ,&nbsp;Qi-Ying Jiang ,&nbsp;Dong-Dong Wu","doi":"10.1016/j.cellsig.2025.111869","DOIUrl":"10.1016/j.cellsig.2025.111869","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent cell death pathway distinct from apoptosis, is crucial in breast cancer (BC) research, especially for overcoming resistance in triple-negative breast cancer (TNBC). Unlike traditional apoptosis, ferroptosis involves the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, iron-driven oxidative reactions, and phospholipid peroxidation. TNBC, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is particularly prone to ferroptosis due to acyl-coenzyme A synthetase (ACSL) 4-related lipid changes and solute carrier family 7 member 11 (SLC7A11)-mediated cystine transport. Recent advancements in biomarkers and therapeutic strategies targeting ferroptosis hold significant promise for the diagnosis and prognosis of TNBC. Notable innovations encompass the development of small-molecule compounds and various methodologies designed to enhance ferroptosis. Combination therapies have demonstrated improved antitumor efficacy by counteracting chemotherapy resistance and inducing immunogenic cell death. Nonetheless, challenges persist in optimizing drug delivery mechanisms and minimizing off-target effects. This review underscores the progress in ferroptosis research and proposes precision oncology strategies that exploit metabolic flexibility in BC, intending to transform TNBC treatment and enhance therapeutic outcomes.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111869"},"PeriodicalIF":4.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085963","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":"Tau deficiency contributes to impaired bone formation via activating PPARγ signaling","authors":"Meipeng Zhu ,&nbsp;Shunze Hu ,&nbsp;Jian Liu ,&nbsp;Hui Huang ,&nbsp;Xuying Sun","doi":"10.1016/j.cellsig.2025.111842","DOIUrl":"10.1016/j.cellsig.2025.111842","url":null,"abstract":"<div><div>Tau protein is enriched in neuronal axons, it functions as a stabilizer of axonal transportation. Hyperphosphorylation of Tau in the brain results in early-onset Alzheimer's disease (AD), causes remarkable bone loss. Notably, pathological Tau leads to the loss of specific physiological Tau that exaggerates Tau toxicity. However, little was known about the physiological role of Tau in bone homeostasis although it's rarely expressed in peripheral tissues. Here, we provided evidence for brain Tau's role in promoting bone formation. Tau knockout (Tau−/−) mice showed smaller body size and exhibited osteoporotic-like deficit, including reduced trabecular and cortical bone mass, especially in young male Tau−/− mice. Such a deficit is likely due to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption in Tau−/− mice. Further mechanistic studies showed increased PPARγ signaling in the brain of Tau−/− mice, which contributed to chemerin release and CMKLR1upregulation in Tau−/− mice brain. Chemerin neutralization remarkably restored osteogenesis potential. Furthermore, reduced repressive H3K9me2 in Tau−/− mice brain led to decreased enrichment of H3K9me2 at PPARγ promoter and thus increased chemerin production. Moreover, PPARγ inhibitor GW9662 significantly reversed the osteoporotic phenotype of Tau−/− mice. Our results implicated brain Tau acting as a dominant positive regulator in bone mass, and unveiled a potential clinical value of PPARγ inhibition in treatment of AD-associated osteoporotic deficits.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"133 ","pages":"Article 111842"},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076304","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":"PRAP1 regulates colorectal cancer cell proliferation and ferroptosis through the Nrf2 signaling pathway","authors":"Hongchao Zhao ,&nbsp;Deyao Zhao ,&nbsp;Siting Li ,&nbsp;Yang Liu ,&nbsp;Ruiwen Zhao ,&nbsp;Xiaorong Zhu ,&nbsp;Pingping Xiong ,&nbsp;Yingyi Mo ,&nbsp;Hao Gu ,&nbsp;Junqi Liu","doi":"10.1016/j.cellsig.2025.111863","DOIUrl":"10.1016/j.cellsig.2025.111863","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer (CRC) is a common type of cancer that impacts the digestive tract, and current treatment options have limitations. Studies have confirmed that ferroptosis plays a key role in CRC progression. This research sought to clarify how Proline-rich acidic protein 1 (PRAP1) influences CRC advancement and ferroptosis, and to uncover the underlying mechanisms involved.</div></div><div><h3>Methods</h3><div>Real-time quantitative PCR (RT-qPCR) and western blot were employed to ascertain the levels of PRAP1 in CRC cells (SW480, SW620, and LOVO) and tissues. Immunofluorescence was utilized to locate PRAP1. Biological characterization of CRC cells was determined through CCK-8 assay, EdU staining, Transwell assay, TUNEL staining and Scratch-wound assay. Iron and Fe²⁺ content was measured using prussian blue staining and iron assay kit. A nude mouse model of xenograft was established, and the impact of PRAP1 on tumor growth was investigated by pathological staining. Expression of ferroptosis-related proteins as well as nuclear factor-erythroid factor 2-related factor 2 (Nrf2) pathway proteins was detected by Western blot.</div></div><div><h3>Results</h3><div>PRAP1 levels were elevated in CRC. Overexpression PRAP1 promoted cell proliferation, inhibited apoptosis and ferroptosis. Additionally, overexpression PRAP1 can activate the Nrf2 pathway. However, silencing PRAP1 had the opposite effect. In vivo tumor xenograft experiments showed that silencing PRAP1 resulted in decreased Ki67 positivity and increased TUNEL positivity in tumor tissues, and blocked Nrf2 pathway, thereby inhibited tumor growth.</div></div><div><h3>Conclusion</h3><div>PRAP1 promotes CRC cell proliferation and inhibits ferroptosis by Nrf2 pathway. This study provides a conceptual framework for the development of novel targeted drugs.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"134 ","pages":"Article 111863"},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076302","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":"MTDH∆7-mediated mTOR activation drives doxorubicin resistance in triple-negative breast cancer: Relevance of mTORC1 inhibition on chemosensitization","authors":"Shashikanta Sahoo ,&nbsp;Sunita Kumari ,&nbsp;Praveen Kumar Neeli ,&nbsp;Sriravali Pulipaka ,&nbsp;Madhusudana Kuncha ,&nbsp;Yogesh Chandra ,&nbsp;Sandhya Annamaneni ,&nbsp;Srigiridhar Kotamraju","doi":"10.1016/j.cellsig.2025.111864","DOIUrl":"10.1016/j.cellsig.2025.111864","url":null,"abstract":"<div><div>Cancer chemoresistance poses a major hurdle in the management of several cancers, including breast cancer. Herein, we identified MTDH∆7, a splice variant of an oncogene, metadherin (MTDH), promotes doxorubicin (Dox)-induced chemoresistance in triple-negative breast cancer (TNBC) cells. Increased MTDH∆7 levels were positively correlated with the elevated levels of ABC transporters like ABCB1, ABCC1, and ABCG2, which in turn caused reduced intracellular Dox accumulation. Interestingly, everolimus, an mTORC1 inhibitor, potentiated Dox-induced cytotoxicity by inhibiting MTDH∆7-mediated increase in the aforementioned ABC transporters. Moreover, MTDH∆7 overexpression increased mTORC1 levels, possibly due to MTDH∆7-induced accentuation of mitochondrial respiration, ATP production, and AMPK inactivation. Mechanistically, enhanced phosphorylation of mTORC1 caused NF-κB-dependent activation of cAMP-regulatory element-binding protein (CREB). Further, activated CREB led to an increase in the levels of ABCB1, ABCC1, and ABCG2. Inhibition of either mTORC1 by everolimus or NF-κB by BAY-11-7082 or CREB by H89 reversed these effects and mitigated MTDH∆7-mediated Dox efflux. Accordingly, while Dox administration alone marginally caused tumor regression in SCID mice bearing LV.MTDH∆7-MDA-MB-231 cells, administration of everolimus greatly sensitized these mice to Dox-induced tumor regression. In agreement, intriguingly, a positive correlation was observed between elevated MTDH∆7, mTORC1 activation, and ABC transporters level in human breast cancer patient cohort tumor samples. Collectively, MTDH∆7, by promoting mTOR signaling causes breast cancer chemoresistance, and that targeting MTDH∆7-mTOR signaling axis effectively enhances chemosensitization.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111864"},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947990","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}