Cell Communication and Signaling最新文献

{"title":"Targeting mitochondrial metabolism by the mitotoxin bromoxib in leukemia and lymphoma cells.","authors":"Laura Schmitt, Karina S Krings, Andre Wolsing, Xabier Buque, Marcel Zimmermann, Hector Flores-Romero, Thomas Lenz, Ilka Lechtenberg, Christoph Peter, Björn Stork, Nicole Teusch, Peter Proksch, Kai Stühler, Ana J García-Sáez, Andreas S Reichert, Patricia Aspichueta, Sanil Bhatia, Sebastian Wesselborg","doi":"10.1186/s12964-024-01913-2","DOIUrl":"10.1186/s12964-024-01913-2","url":null,"abstract":"<p><p>Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"541"},"PeriodicalIF":8.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633241","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":"IGFBP7 is a key component of the senescence-associated secretory phenotype (SASP) that induces senescence in healthy cells by modulating the insulin, IGF, and activin A pathways.","authors":"Yesuf Siraj, Domenico Aprile, Nicola Alessio, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi","doi":"10.1186/s12964-024-01921-2","DOIUrl":"10.1186/s12964-024-01921-2","url":null,"abstract":"<p><p>Senescent cells exert their effects through the release of various factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The SASP can induce senescence in healthy cells (secondary senescence), modulate immune system function, reshape the extracellular matrix, and facilitate cancer progression.Among SASP components, certain factors act as key regulators in the induction of secondary senescence. In this study, we evaluated the role of IGFBP7, a crucial SASP component. Our results demonstrated that ROS-prostaglandin signaling is involved in the release of IGFBP7. Furthermore, neutralizing antibodies targeting IGFBP7 attenuated the SASP's pro-senescence activity. Cells incubated with IGFBP7 also entered a state of senescence.The senescence induced by IGFBP7 appears to be mediated through three primary pathways. First, IGFBP7 can bind to insulin, thereby inhibiting its anti-senescence and pro-growth effects. In addition to this inhibitory effect on the insulin pathway, IGFBP7 may enhance IGFII pro-senescence signaling by promoting its interaction with IGF2R while blocking IGF1R. These activities are dependent on ERK and AKT signaling pathways. Finally, IGFBP7 and Activin A, both of which can induce cellular senescence, appear to regulate and inhibit each other, suggesting a compensatory mechanism to prevent excessive senescence. Notably, our preliminary data indicate that IGFBP7, in addition to blocking Activin A, may interact with its receptors and induce senescence via SMAD pathways.Our findings highlight that IGFBP7, along with other members of the IGFBP family, plays a pivotal role in senescence-related signaling pathways. Therefore, IGFBP7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence on tissues and organs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"540"},"PeriodicalIF":8.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633236","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":"Emerging roles and biomarker potential of WNT6 in human cancers.","authors":"Joana M Ferreira, Céline S Gonçalves, Bruno M Costa","doi":"10.1186/s12964-024-01892-4","DOIUrl":"10.1186/s12964-024-01892-4","url":null,"abstract":"<p><p>The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"538"},"PeriodicalIF":8.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633232","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":"Novel Ser74 of NF-κB/IκBα phosphorylated by MAPK/ERK regulates temperature adaptation in oysters.","authors":"Chaogang Wang, Zhuxiang Jiang, Mingyang Du, Rihao Cong, Wei Wang, Taiping Zhang, Jincheng Chen, Guofan Zhang, Li Li","doi":"10.1186/s12964-024-01923-0","DOIUrl":"10.1186/s12964-024-01923-0","url":null,"abstract":"<p><p>Phosphorylation of Ser32 and Ser36 controls the degradation of IκBα is the conserved cascade mechanisms of immune core signaling pathway, NF-κB pathway in metazoans, but it's response to abiotic stress and the presence of novel phosphorylation mechanisms in other species remain unclear. Herein, we reported a novel heat-induced phosphorylation site (Ser74) at oysters' major IκBα, which independently regulated ubiquitination-proteasome degradation without the requirement of phosphorylation at S32 and S36. And this site was phosphorylated by ERK/MAPK pathway, which then promoted REL nuclear translocation to activate cell survival related genes to defend heat-stress. The MAPK-NF-κB cascade exhibited divergent thermal responses and adaptation patterns between two congeneric oyster species with differential habitat temperatures, indicating its involvement in shaping temperature adaptation. This study demonstrated that the existence of complex and unique phosphorylation-mediated signaling transduction mechanism in marine invertebrates, and expanded our understanding of the evolution and function of established classical pathway crosstalk mechanisms.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"539"},"PeriodicalIF":8.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633239","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":"Cell damage shifts the microRNA content of small extracellular vesicles into a Toll-like receptor 7-activating cargo capable to propagate inflammation and immunity.","authors":"Valentina Salvi, Carolina Gaudenzi, Barbara Mariotti, Gaia Giongrandi, Silvia Alacqua, Veronica Gianello, Tiziana Schioppa, Laura Tiberio, Angela Ceribelli, Carlo Selmi, Paolo Bergese, Stefano Calza, Annalisa Del Prete, Silvano Sozzani, Flavia Bazzoni, Daniela Bosisio","doi":"10.1186/s12964-024-01924-z","DOIUrl":"10.1186/s12964-024-01924-z","url":null,"abstract":"<p><strong>Background: </strong>The physiological relevance of cell-to-cell communication mediated by small extracellular vesicle-encapsulated microRNAs (sEV-miRNAs) remains debated because of the limiting representativity of specific miRNAs within the extracellular pool. We hypothesize that sEV-miRNA non-canonical function consisting of the stimulation of Toll-like receptor 7 (TLR7) may rely on a global shift of the sEV cargo rather than on the induction of one or few specific miRNAs. Psoriasis represents an ideal model to test such hypothesis as it is driven by overt activation of TLR7-expressing plasmacytoid dendritic cells (pDCs) following keratinocyte damage.</p><p><strong>Methods: </strong>To mimic the onset of psoriasis, keratinocytes were treated with a cocktail of psoriatic cytokines or UV-irradiated. SmallRNA sequencing was performed on sEVs released by healthy and UV-treated keratinocytes. sEV-miRNAs were analyzed for nucleotide composition as well as for the presence of putative TLR7-binding triplets. Primary human pDCs where stimulated with sEVs +/- inhibitors of TLR7 (Enpatoran), of sEV release (GW4869 + manumycin) and of TLR7-mediated pDC activation (anti-BDCA-2 antibody). Secretion of type I IFNs and activation of CD8⁺T cells were used as readouts. qPCR on psoriatic and healthy skin biopsies was conducted to identify induced miRNAs.</p><p><strong>Results: </strong>sEV-miRNAs released by damaged keratinocytes revealed a significantly higher content of TLR7-activating sequences than healthy cells. As expected, differential expression analysis confirmed the presence of miRNAs upregulated in psoriatic skin, including miR203a. More importantly, 76.5% of induced miRNAs possessed TLR7-binding features and among these we could detect several previously demonstrated TLR7 ligands. In accordance with this in silico analysis, sEVs from damaged keratinocytes recapitulated key events of psoriatic pathogenesis by triggering pDCs to release type I interferon and activate cytotoxic CD8⁺T cells in a TLR7- and sEV-dependent manner.</p><p><strong>Discussion: </strong>Our results demonstrate that miR203a is just one paradigmatic TLR7-activating miRNA among the hundreds released by UV-irradiated keratinocytes, which altogether trigger pDC activation in psoriatic conditions. This represents the first evidence that cell damage shifts the miRNA content of sEVs towards a TLR7-activating cargo capable to propagate inflammation and immunity, offering strong support to the physiological role of systemic miRNA-based cell-to-cell communication.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"536"},"PeriodicalIF":8.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11545887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633230","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":"NAD⁺ enhancers as therapeutic agents in the cardiorenal axis.","authors":"Mariano Marín-Blázquez, Jordi Rovira, María José Ramírez-Bajo, Rubén Zapata-Pérez, Rubén Rabadán-Ros","doi":"10.1186/s12964-024-01903-4","DOIUrl":"10.1186/s12964-024-01903-4","url":null,"abstract":"<p><p>Cardiorenal diseases represent a complex interplay between heart failure and renal dysfunction, being clinically classified as cardiorenal syndromes (CRS). Recently, the contributions of altered nicotinamide adenine dinucleotide (NAD⁺) metabolism, through deficient NAD⁺ synthesis and/or elevated consumption, have proved to be decisive in the onset and progress of cardiorenal disease. NAD⁺ is a pivotal coenzyme in cellular metabolism, being significant in various signaling pathways, such as energy metabolism, DNA damage repair, gene expression, and stress response. Convincing evidence suggests that strategies designed to boost cellular NAD⁺ levels are a promising therapeutic option to address cardiovascular and renal disorders. Here, we review and discuss the implications of NAD⁺ metabolism in cardiorenal diseases, focusing on the propitious NAD⁺ boosting therapeutic strategies, based on the use of NAD⁺ precursors, poly(ADP-ribose) polymerase inhibitors, sirtuin activators, and other alternative approaches, such as CD38 blockade, nicotinamide phosphoribosyltransferase activation and combined interventions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"537"},"PeriodicalIF":8.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11546376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633238","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":"Inhibition of SGLT2 protects podocytes in diabetic kidney disease by rebalancing mitochondria-associated endoplasmic reticulum membranes.","authors":"Xuehong Li, Qiong Li, Xinying Jiang, Shicong Song, Wei Zou, Qinglan Yang, Sirui Liu, Shuangqin Chen, Cheng Wang","doi":"10.1186/s12964-024-01914-1","DOIUrl":"10.1186/s12964-024-01914-1","url":null,"abstract":"<p><strong>Background: </strong>Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes.</p><p><strong>Methods: </strong>We assessed MAMs formation in podocytes from DKD patients' renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes.</p><p><strong>Results: </strong>MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect.</p><p><strong>Conclusions: </strong>Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"534"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607526","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":"RNF13 protects neurons against ischemia-reperfusion injury via stabilizing p62-mediated Nrf2/HO-1 signaling pathway.","authors":"Qiangping Wang, Shuang Li, Wenjie Wu, Wenke Zhou, Kaixuan Yan, Zhen Liu, Lanlan Yan, Baoping Zheng, Fangcheng Zhang, Xiaobing Jiang, Youfan Ye, Haijun Wang","doi":"10.1186/s12964-024-01905-2","DOIUrl":"10.1186/s12964-024-01905-2","url":null,"abstract":"<p><strong>Background: </strong>Cerebral ischemia/reperfusion injury (CIRI), a common, universal clinical problem that costs a large proportion of the economic and disease burden. Identifying the key regulators of cerebral I/R injury could provide potential strategies for clinically improving the prognosis of stroke. Ring finger protein 13 (RNF13) has been proven to be involved in the inflammatory response. Here, we aimed to identify the role of RNF13 in cerebral I/R injury and further reveal its immanent mechanisms.</p><p><strong>Methods: </strong>The CRISPR/Cas9 based knockout mice, RNA sequencing, mass spectrometry, co-immunoprecipitation, GST-pull down, immunofluorescent staining, western blot, RT-PCR were used to investigate biodistribution, function and mechanism of RNF13 during cerebral I/R injury.</p><p><strong>Results: </strong>In the present study, we found that RNF13 was significantly up-regulated in patients, mice and primary neurons after I/R injury. Deficiency of RNF13 aggravated I/R-induced neurological impairment, inflammatory response and apoptosis while overexpression of RNF13 inhibited I/R injury. Mechanistically, this inhibitory effect of RNF13 during I/R injury was confirmed to be dependent on the blocking of TRIM21-mediated autophagy-dependent degradation of p62 and the stabilization of the p62-mediated Nrf2/HO-1 signaling pathway.</p><p><strong>Conclusion: </strong>RNF13 is a crucial regulator of cerebral I/R injury that plays its role in inhibiting cell apoptosis and inflammatory response by preventing the autophagy-medicated degradation of the p62/Nrf2/HO-1 signaling pathway via blocking the interaction of TRIM21-p62 complex. Therefore, RNF13 represents a potential pharmacological target in acute ischemia stroke therapy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"535"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607527","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":"Breast cancer cells utilize T3 to trigger proliferation through cellular Ca²⁺ modulation.","authors":"Ines Tawfik, Katharina Schlick, Julian Ostaku, Doruntina Bresilla, Sonja Gabrijelčič, Benjamin Gottschalk, Alwin Sokolowski, Ernst Malle, Katarina Kalinova, Martin Hirtl, Corina T Madreiter-Sokolowski","doi":"10.1186/s12964-024-01917-y","DOIUrl":"10.1186/s12964-024-01917-y","url":null,"abstract":"<p><p>High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca²⁺ handling proteins, thereby boosting mitochondrial Ca²⁺ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca²⁺-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca²⁺ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"533"},"PeriodicalIF":8.2,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591070","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":"Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis.","authors":"Hyun Jeong Seok, Jae Yeon Choi, Dong Hyeon Lee, Incheol Shin, In Hwa Bae","doi":"10.1186/s12964-024-01915-0","DOIUrl":"10.1186/s12964-024-01915-0","url":null,"abstract":"<p><strong>Background: </strong>Resistance acquired after radiotherapy is directly related to the failure of various cancer treatments, including GBM. Because the mechanism for overcoming radioresistance has not yet been clearly identified, the development of diagnostic and therapeutic markers to treat radioresistance is necessary. Since increased expression of stemness- and EMT-related markers are reported to be closely correlated with radioresistance, research is underway to develop new drugs targeting these factors.</p><p><strong>Methods: </strong>To develop an anticancer drug that overcomes radioresistance, a library of drugs already approved by the FDA was used. After treating radioresistant GBM cells with each drug, the expression of stemness- and EMT-related markers was confirmed by qRT-PCR, and as a result, Atomoxetine (ATX) was selected. It was confirmed that radioresistance-induced cell migratory, invasive, sphere formation abilities, and tumor growth using a xenograft mouse model were suppressed upon ATX treatment. Using a miRNA prediction tool, we discovered miR-520d-5p, which targets Notch2 and Hey1, key factors in radioresistance, and discovered circATIC targeting this miRNA, revealing its relationship with ATX. We demonstrated the expression regulation mechanism and signaling mechanism between circATIC, miR-520d-5p, Notch2, and Hey1 factors using a luciferase reporter assay. In addition, the results at the cellular level were clinically verified by confirming the correlation between radiation, miR-520d-5p, and circATIC using patient plasma by qRT-PCR.</p><p><strong>Results: </strong>ATX showed potential as a treatment for radioresistance by suppressing the malignant phenotype by regulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling mechanism in vitro and in vivo using radioresistant GBM cells.</p><p><strong>Conclusions: </strong>This study revealed that ATX suppresses radioresistance through the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway. These results showed the potential of ATX as a new drug that can overcome radioresistance, a major challenge in cancer treatment, and the signaling factors identified in this mechanism suggest the possibility of use as potential targets for the diagnosis and treatment of radioresistance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"532"},"PeriodicalIF":8.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584950","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}