Mitochondria-targeting agents, known as mitocans, are emerging as potent cancer therapeutics due to pronounced metabolic and apoptotic adaptations in the mitochondria of cancer cells. ONC212, an imipridone-family compound initially identified as a ClpP agonist, is currently under investigation as a potential mitocan with demonstrated preclinical efficacy against multiple malignancies. Despite this efficacy, the molecular mechanism underlying the cell death induced by ONC212 remains unclear. This study systematically investigates the mitochondrial involvement and signaling cascades associated with ONC212-induced cell death, utilizing HeLa and A549 cancer cells. Treated cancer cells exhibited characteristic apoptotic features, such as annexin-V positivity and caspase-3 activation; however, these occurred independently of typical mitochondrial events like membrane potential loss (ΔΨm) and cytochrome c release, as well as caspase-8 activation associated with the extrinsic pathway. Additionally, ONC212 treatment increased the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, which impeded apoptosis, as the overexpression of Bcl-2-GFP and Bcl-xL-GFP significantly reduced ONC212-mediated cell death. Furthermore, combining a sub-lethal dose of the Bcl-2/Bcl-xL inhibitor Navitoclax with ONC212 markedly augmented caspase-3 activation and cell death, still without any notable ΔΨm loss or cytochrome c release. Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling.
{"title":"ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation","authors":"Vishal Basu, Shabnam, Yamini Murghai, Maqsood Ali, Swetangini Sahu, Bhupendra K. Verma, Mahendra Seervi","doi":"10.1186/s12964-024-01817-1","DOIUrl":"https://doi.org/10.1186/s12964-024-01817-1","url":null,"abstract":"Mitochondria-targeting agents, known as mitocans, are emerging as potent cancer therapeutics due to pronounced metabolic and apoptotic adaptations in the mitochondria of cancer cells. ONC212, an imipridone-family compound initially identified as a ClpP agonist, is currently under investigation as a potential mitocan with demonstrated preclinical efficacy against multiple malignancies. Despite this efficacy, the molecular mechanism underlying the cell death induced by ONC212 remains unclear. This study systematically investigates the mitochondrial involvement and signaling cascades associated with ONC212-induced cell death, utilizing HeLa and A549 cancer cells. Treated cancer cells exhibited characteristic apoptotic features, such as annexin-V positivity and caspase-3 activation; however, these occurred independently of typical mitochondrial events like membrane potential loss (ΔΨm) and cytochrome c release, as well as caspase-8 activation associated with the extrinsic pathway. Additionally, ONC212 treatment increased the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, which impeded apoptosis, as the overexpression of Bcl-2-GFP and Bcl-xL-GFP significantly reduced ONC212-mediated cell death. Furthermore, combining a sub-lethal dose of the Bcl-2/Bcl-xL inhibitor Navitoclax with ONC212 markedly augmented caspase-3 activation and cell death, still without any notable ΔΨm loss or cytochrome c release. Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182123","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}
Pub Date : 2024-09-11DOI: 10.1186/s12964-024-01814-4
Venkataragavan Chandrasekaran, Karin M. E. Andersson, Malin Erlandsson, Shuxiang Li, Torbjörn Nur Olsson, Maria-Jose Garcia-Bonete, Eric Malmhäll-Bah, Pegah Johansson, Gergely Katona, Maria I. Bokarewa
Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.
染色质二价区（BvCR）的特征是组蛋白 H3 上的三甲基化赖氨酸 4（H3K4me3）和赖氨酸 27（H3K27me3）沉积，有助于细胞分化过程中的基因表达控制。BvCR 在转录后 DNA 损伤反应中的作用仍未确定。肿瘤蛋白存活素与染色质结合，并在 CD4+ 细胞中介导 IFNγ 的效应。本研究探讨了 BvCR 在类风湿性关节炎（RA）自身免疫 CD4+ 细胞 DNA 损伤反应中的作用。我们对人类 CD4+ 细胞中与存活素结合的染色质、H3K4me3、H3K27me3 和 H3K27ac 进行了深度测序，发现 BvCR 具有这三种组蛋白 H3 修饰。通过整合主题富集分析、计算机器学习和结构建模，预测了染色质上存活素的蛋白伴侣，并通过质谱和肽结合阵列进行了实验验证。在使用存活素抑制剂处理的CD4+细胞中，研究了存活素依赖的BvCR变化和BvCR控制的基因转录，揭示了存活素依赖的生物学过程。最后，我们将生存素依赖过程绘制到了 RA 患者血液和滑膜组织中 CD4+ 细胞的转录组中，并探讨了现代免疫调节药物对这些过程的影响。我们发现，以 H3K4me3 为主导的 BvCR（H3K4me3-BvCR）将存活素容纳在控制 DNA 损伤的基因的顺式调控元件中。抑制存活素或JAK-STAT信号增强了H3K4me3-BvCR的优势，从而改善了DNA损伤识别能力，并阻止了培养的CD4+细胞的细胞周期进展。具体来说，BvCR容纳survivin有助于BRG1/SWI染色质重塑复合物的序列特异性锚定，从而协调DNA损伤反应。绘制存活素与BRG1/SWI复合物的相互作用组图显示了存活素与将复合物锚定在染色质上的亚基的相互作用。在CD4+细胞中联合表达BRG1、survivin和IFNγ可完全抑制RA的DNA损伤反应。这些细胞具有很强的RA关节归巢能力。免疫调节药物抑制了BRG1/SWI复合物的锚定亚基，从而影响了CD4+细胞的致关节炎特征。BvCR执行DNA损伤控制，以维持IFN激活的CD4+细胞基因组的保真度。Survivin 将 BRG1/SWI 复合物锚定在 BvCR 上，以抑制 DNA 损伤反应。这些结果为针对自身免疫中的存活素和BRG1/SWI复合物的治疗干预提供了一个平台。
{"title":"Bivalent chromatin accommodates survivin and BRG1/SWI complex to activate DNA damage response in CD4+ cells","authors":"Venkataragavan Chandrasekaran, Karin M. E. Andersson, Malin Erlandsson, Shuxiang Li, Torbjörn Nur Olsson, Maria-Jose Garcia-Bonete, Eric Malmhäll-Bah, Pegah Johansson, Gergely Katona, Maria I. Bokarewa","doi":"10.1186/s12964-024-01814-4","DOIUrl":"https://doi.org/10.1186/s12964-024-01814-4","url":null,"abstract":"Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182124","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}
Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53–75 and 85–107) directly interacts with the C-terminal region of TAK1 (amino acids 1–300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.
{"title":"TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression","authors":"Bin-Bin Zhang, Yi-Lin Zhao, Yan-Yu Lu, Ji-Hong Shen, Hui-Yong Li, Han-Xue Zhang, Xiao-Yue Yu, Wen-Cai Zhang, Gang Li, Zhan-Ying Han, Sen Guo, Xu-Tao Zhang","doi":"10.1186/s12964-024-01816-2","DOIUrl":"https://doi.org/10.1186/s12964-024-01816-2","url":null,"abstract":"Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53–75 and 85–107) directly interacts with the C-terminal region of TAK1 (amino acids 1–300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223790","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}
Pub Date : 2024-09-11DOI: 10.1186/s12964-024-01815-3
Annan Chen, Jian Zhang, Zhixin Yan, Yufei Lu, Weize Chen, Yingxue Sun, Qiuyu Gu, Fang Li, Yan Yang, Shanfang Qiu, Xueping Lin, Dong Zhang, Jie Teng, Yi Fang, Bo Shen, Nana Song, Xiaoqiang Ding
<p><b>Correction: Cell Commun Signal (2024) 22, 393</b></p><p>https://doi.org/10.1186/s12964-024-01773-w</p><p>Following the publication of the original article [1], the authors noticed that the acknowledgments section was inadvertently omitted. We sincerely apologize for this oversight. The missing acknowledgments are given in this correction article. </p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>Chen A, Zhang J, Yan Z, et al. Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1. Cell Commun Signal. 2024;22:393. https://doi.org/10.1186/s12964-024-01773-w.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><p>We would like to express our deepest gratitude to Professor Liming Zhang, Dr. Yue Wang, and Dr. Yanlin Li (East China Normal University, China) for technical assistance in detecting pH value of ranal tissue by the Hemin/CNF microelectrode. We are also deeply thankful to Researcher Shuan Zhao and Dr. Zhouping Zou (Zhongshan Hospital, Fudan University, China) for their generous provision of critical experimental materials. This work was supported by grants from the National Natural Science Foundation of China (82070710), Shanghai Science and Technology Innovation Action Plan (21S219029001 and 22410714200), Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Science and Technology Commission (20DZ2271600), Shanghai Municipal Hospital Frontier Technology Project supported by Shanghai Shen Kang Hospital Development Center (SHDC2202230), Natural Science Foundation of Fujian Province (2022J011419), and Shanghai Municipal Key Clinical Specialty (shslczdzk02501).</p><span>Author notes</span><ol><li><p>Annan Chen, Jian Zhang and Zhixin Yan contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney, Shanghai Institute of Kidney and Dialysis, Shanghai Key Laboratory of Kidney and Blood Purification, Hemodialysis Quality Control Center of Shanghai, Shanghai, China</p><p>Annan Chen, Jian Zhang, Zhixin Yan, Yufei Lu, Weize Chen, Yingxue Sun, Qiuyu Gu, Fang Li, Yan Yang, Jie Teng, Yi Fang, Bo Shen, Nana Song & Xiaoqiang Ding</p></li><li><p>Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China</p><p>Shanfang Qiu, Xueping Lin, Dong Zhang & Jie Teng</p></li><li><p>Fudan Zhangjiang Institute, Shanghai, China</p><p>Nana Song</p></li><li><p>Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, PR China</p><p>Bo Shen, Nana Song & Xiaoq
更正：Cell Commun Signal (2024) 22, 393https://doi.org/10.1186/s12964-024-01773-wFollowing 原文[1]发表后，作者发现致谢部分被无意遗漏。我们对这一疏忽表示诚挚的歉意。本更正文章给出了遗漏的致谢部分。Chen A, Zhang J, Yan Z, et al. Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1.Cell Commun Signal.2024;22:393. https://doi.org/10.1186/s12964-024-01773-w.Article CAS PubMed PubMed Central Google Scholar 下载参考文献我们衷心感谢华东师范大学张黎明教授、王悦博士和李彦林博士在使用 Hemin/CNF 微电极检测肾组织 pH 值方面提供的技术帮助。同时，我们也非常感谢赵爽研究员和邹周平博士（复旦大学附属中山医院）慷慨提供的关键实验材料。本研究得到了国家自然科学基金（82070710）、上海市科技创新行动计划（21S219029001和22410714200）、上海市科委肾脏与血液净化重点实验室（20DZ2271600）、上海市申康医院发展中心支持的上海市医院前沿技术项目（SHDC2202230）、福建省自然科学基金（2022J011419）和上海市临床重点专科（shslczdzk02501）的资助。作者简介陈安南、张健和严志新对本研究做出了同等贡献。作者及工作单位复旦大学附属中山医院肾内科、上海市肾脏病医疗中心、上海市肾脏病与透析研究所、上海市肾脏与血液净化重点实验室、上海市血液透析质量控制中心 陈安南 张健 严志新 陆宇飞 陈伟泽 孙映雪 顾秋玉 李芳 杨艳 滕杰 方毅 沈波 宋娜娜 &；丁小强复旦大学附属中山医院厦门分院肾内科邱善芳、林雪萍、张东、滕杰复旦大学张江研究院，上海，中国宋娜娜复旦大学附属中山医院肾内科沈波、宋娜娜，上海，中华人民共和国丁小强作者陈安楠查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者张健查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者颜志新查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者陆宇飞查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者陈伟泽查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Yingxue Sun查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Qiuyu Gu查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Fang Li查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Yan Yang查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者发表作品您也可以在 PubMed Google Scholar中搜索该作者邱善芳查看作者发表作品您也可以在 PubMed Google Scholar中搜索该作者林雪萍查看作者发表作品您也可以在 PubMed Google Scholar中搜索该作者张东查看作者发表作品您也可以在 PubMed Google Scholar中搜索该作者滕杰查看作者发表作品您也可以在 PubMed Google Scholar中搜索该作者易奕方方查看作者发表的论文您也可以在 PubMed Google Scholar中搜索该作者沈波查看作者发表的论文您也可以在 PubMed Google Scholar中搜索该作者宋娜娜查看作者发表的论文您也可以在 PubMed Google Scholar中搜索该作者丁晓强查看作者发表的论文您也可以在 PubMed Google Scholar中搜索该作者通讯作者：沈波、宋娜娜或丁小强。出版者注释施普林格-自然对出版地图和机构隶属关系中的管辖权主张保持中立。原文的在线版本可在以下网址找到： https://doi.org/10.1186/s12964-024-01773-w.Open Access 本文采用知识共享署名-非商业性-禁止衍生 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式进行任何非商业性使用、共享、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明您是否修改了许可材料。根据本许可协议，您无权分享从本文或其中部分内容衍生的改编材料。
{"title":"Correction: Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1","authors":"Annan Chen, Jian Zhang, Zhixin Yan, Yufei Lu, Weize Chen, Yingxue Sun, Qiuyu Gu, Fang Li, Yan Yang, Shanfang Qiu, Xueping Lin, Dong Zhang, Jie Teng, Yi Fang, Bo Shen, Nana Song, Xiaoqiang Ding","doi":"10.1186/s12964-024-01815-3","DOIUrl":"https://doi.org/10.1186/s12964-024-01815-3","url":null,"abstract":"<p><b>Correction: Cell Commun Signal (2024) 22, 393</b></p><p>https://doi.org/10.1186/s12964-024-01773-w</p><p>Following the publication of the original article [1], the authors noticed that the acknowledgments section was inadvertently omitted. We sincerely apologize for this oversight. The missing acknowledgments are given in this correction article. </p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Chen A, Zhang J, Yan Z, et al. Acidic preconditioning induced intracellular acid adaptation to protect renal injury via dynamic phosphorylation of focal adhesion kinase-dependent activation of sodium hydrogen exchanger 1. Cell Commun Signal. 2024;22:393. https://doi.org/10.1186/s12964-024-01773-w.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><p>We would like to express our deepest gratitude to Professor Liming Zhang, Dr. Yue Wang, and Dr. Yanlin Li (East China Normal University, China) for technical assistance in detecting pH value of ranal tissue by the Hemin/CNF microelectrode. We are also deeply thankful to Researcher Shuan Zhao and Dr. Zhouping Zou (Zhongshan Hospital, Fudan University, China) for their generous provision of critical experimental materials. This work was supported by grants from the National Natural Science Foundation of China (82070710), Shanghai Science and Technology Innovation Action Plan (21S219029001 and 22410714200), Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Science and Technology Commission (20DZ2271600), Shanghai Municipal Hospital Frontier Technology Project supported by Shanghai Shen Kang Hospital Development Center (SHDC2202230), Natural Science Foundation of Fujian Province (2022J011419), and Shanghai Municipal Key Clinical Specialty (shslczdzk02501).</p><span>Author notes</span><ol><li><p>Annan Chen, Jian Zhang and Zhixin Yan contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai Medical Center of Kidney, Shanghai Institute of Kidney and Dialysis, Shanghai Key Laboratory of Kidney and Blood Purification, Hemodialysis Quality Control Center of Shanghai, Shanghai, China</p><p>Annan Chen, Jian Zhang, Zhixin Yan, Yufei Lu, Weize Chen, Yingxue Sun, Qiuyu Gu, Fang Li, Yan Yang, Jie Teng, Yi Fang, Bo Shen, Nana Song & Xiaoqiang Ding</p></li><li><p>Department of Nephrology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China</p><p>Shanfang Qiu, Xueping Lin, Dong Zhang & Jie Teng</p></li><li><p>Fudan Zhangjiang Institute, Shanghai, China</p><p>Nana Song</p></li><li><p>Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, PR China</p><p>Bo Shen, Nana Song & Xiaoq","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182125","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}
Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma.
{"title":"A novel amphiphilic squalene-based compound with open-chain polyethers reduces malignant melanoma metastasis in-vitro and in-vivo","authors":"Yaman Zhang, Meriem Bejaoui, Tran Ngoc Linh, Takashi Arimura, Hiroko Isoda","doi":"10.1186/s12964-024-01813-5","DOIUrl":"https://doi.org/10.1186/s12964-024-01813-5","url":null,"abstract":"Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182126","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}
Pub Date : 2024-09-10DOI: 10.1186/s12964-024-01792-7
Xiangyu Wang, Yinuo Li, Xin Hou, Jingfang Li, Xiangyi Ma
Endometrial cancer is one of the major gynecological cancers, with increasing incidence and mortality in the past decades. Emerging preclinical and clinical data have indicated its close association with obesity and dyslipidemia. Metabolism reprogramming has been considered as the hallmark of cancer, to satisfy the extensive need of nutrients and energy for survival and growth. Particularly, lipid metabolism reprogramming has aroused the researchers’ interest in the field of cancer, including tumorigenesis, invasiveness, metastasis, therapeutic resistance and immunity modulation, etc. But the roles of lipid metabolism reprogramming in endometrial cancer have not been fully understood. This review has summarized how lipid metabolism reprogramming induces oncogenesis and progression of endometrial cancer, including the biological functions of aberrant lipid metabolism pathway and altered transcription regulation of lipid metabolism pathway. Besides, we proposed novel therapeutic strategies of targeting lipid metabolism pathway and concentrated on its potential of sensitizing immunotherapy and hormonal therapy, to further optimize the existing treatment modalities of patients with advanced/metastatic endometrial cancer. Moreover, we expect that targeting lipid metabolism plus hormone therapy may block the endometrial malignant transformation and enrich the preventative approaches of endometrial cancer. Lipid metabolism reprogramming plays an important role in tumor initiation and cancer progression of endometrial cancer. Targeting the core enzymes and transcriptional factors of lipid metabolism pathway alone or in combination with immunotherapy/hormone treatment is expected to decrease the tumor burden and provide promising treatment opportunity for patients with advanced/metastatic endometrial cancer.
{"title":"Lipid metabolism reprogramming in endometrial cancer: biological functions and therapeutic implications","authors":"Xiangyu Wang, Yinuo Li, Xin Hou, Jingfang Li, Xiangyi Ma","doi":"10.1186/s12964-024-01792-7","DOIUrl":"https://doi.org/10.1186/s12964-024-01792-7","url":null,"abstract":"Endometrial cancer is one of the major gynecological cancers, with increasing incidence and mortality in the past decades. Emerging preclinical and clinical data have indicated its close association with obesity and dyslipidemia. Metabolism reprogramming has been considered as the hallmark of cancer, to satisfy the extensive need of nutrients and energy for survival and growth. Particularly, lipid metabolism reprogramming has aroused the researchers’ interest in the field of cancer, including tumorigenesis, invasiveness, metastasis, therapeutic resistance and immunity modulation, etc. But the roles of lipid metabolism reprogramming in endometrial cancer have not been fully understood. This review has summarized how lipid metabolism reprogramming induces oncogenesis and progression of endometrial cancer, including the biological functions of aberrant lipid metabolism pathway and altered transcription regulation of lipid metabolism pathway. Besides, we proposed novel therapeutic strategies of targeting lipid metabolism pathway and concentrated on its potential of sensitizing immunotherapy and hormonal therapy, to further optimize the existing treatment modalities of patients with advanced/metastatic endometrial cancer. Moreover, we expect that targeting lipid metabolism plus hormone therapy may block the endometrial malignant transformation and enrich the preventative approaches of endometrial cancer. Lipid metabolism reprogramming plays an important role in tumor initiation and cancer progression of endometrial cancer. Targeting the core enzymes and transcriptional factors of lipid metabolism pathway alone or in combination with immunotherapy/hormone treatment is expected to decrease the tumor burden and provide promising treatment opportunity for patients with advanced/metastatic endometrial cancer.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182129","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}
Pub Date : 2024-09-09DOI: 10.1186/s12964-024-01785-6
Jeeshan Singh, Leticija Zlatar, Marco Muñoz-Becerra, Günter Lochnit, Irmgard Herrmann, Felix Pfister, Christina Janko, Jasmin Knopf, Moritz Leppkes, Janina Schoen, Luis E. Muñoz, Georg Schett, Martin Herrmann, Christine Schauer, Aparna Mahajan
The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.
中性粒细胞胞外捕获物（NET）形成的诱导因素多种多样，因此，并不存在NET形成不可或缺的特定途径或标志性分子。但是，组蛋白修饰、染色质解聚、核膜破坏和 NET 释放等某些事件却无处不在。在 NET 形成过程中，中性粒细胞会大幅重新排列其细胞质、颗粒和核内容。然而，NET形成过程中每个步骤的确切解码机制仍未确定。在此，我们研究了NET形成过程中核包膜破裂的机制。免疫荧光显微镜评估显示，在NET形成过程中，核外膜蛋白nesprin-1逐渐解体，核形态也发生了改变。对各种诱导剂产生的NET进行的MALDI-TOF分析检测到了nesprin-1片段的积累。这表明nesprin-1降解发生在NET释放之前。在钙蛋白酶-1抑制剂存在的情况下，钙驱动的NET形成过程中内斯普林-1降解减少。显微镜评估证实，层粘连蛋白 B 受体（LBR）的解体和肌动蛋白细胞骨架的崩溃分别发生在 NET 释放的早期和晚期阶段。我们的结论是，钙蛋白酶-1能降解内斯普林-1，协调核膜的减弱，促进LBR的解体，促进DNA的释放，并最终促进NET的形成。
{"title":"Calpain-1 weakens the nuclear envelope and promotes the release of neutrophil extracellular traps","authors":"Jeeshan Singh, Leticija Zlatar, Marco Muñoz-Becerra, Günter Lochnit, Irmgard Herrmann, Felix Pfister, Christina Janko, Jasmin Knopf, Moritz Leppkes, Janina Schoen, Luis E. Muñoz, Georg Schett, Martin Herrmann, Christine Schauer, Aparna Mahajan","doi":"10.1186/s12964-024-01785-6","DOIUrl":"https://doi.org/10.1186/s12964-024-01785-6","url":null,"abstract":"The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182130","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}
Bone sarcomas are malignant tumors of mesenchymal origin. Complete surgical resection is the cornerstone of multidisciplinary treatment. However, advanced, unresectable forms remain incurable. A crucial step towards addressing this challenge involves comprehending the molecular mechanisms underpinning tumor progression and metastasis, laying the groundwork for innovative precision medicine-based interventions. We previously showed that tyrosine kinase receptor Ephrin Type-A Receptor 2 (EphA2) is overexpressed in bone sarcomas. EphA2 is a key oncofetal protein implicated in metastasis, self-renewal, and chemoresistance. Molecular, genetic, biochemical, and pharmacological approaches have been developed to target EphA2 and its signaling pathway aiming to interfere with its tumor-promoting effects or as a carrier for drug delivery. This review synthesizes the main functions of EphA2 and their relevance in bone sarcomas, providing strategies devised to leverage this receptor for diagnostic and therapeutic purposes, with a focus on its applicability in the three most common bone sarcoma histotypes: osteosarcoma, chondrosarcoma, and Ewing sarcoma.
{"title":"Targeting the EphA2 pathway: could it be the way for bone sarcomas?","authors":"Giorgia Giordano, Cristina Tucciarello, Alessandra Merlini, Santina Cutrupi, Ymera Pignochino","doi":"10.1186/s12964-024-01811-7","DOIUrl":"https://doi.org/10.1186/s12964-024-01811-7","url":null,"abstract":"Bone sarcomas are malignant tumors of mesenchymal origin. Complete surgical resection is the cornerstone of multidisciplinary treatment. However, advanced, unresectable forms remain incurable. A crucial step towards addressing this challenge involves comprehending the molecular mechanisms underpinning tumor progression and metastasis, laying the groundwork for innovative precision medicine-based interventions. We previously showed that tyrosine kinase receptor Ephrin Type-A Receptor 2 (EphA2) is overexpressed in bone sarcomas. EphA2 is a key oncofetal protein implicated in metastasis, self-renewal, and chemoresistance. Molecular, genetic, biochemical, and pharmacological approaches have been developed to target EphA2 and its signaling pathway aiming to interfere with its tumor-promoting effects or as a carrier for drug delivery. This review synthesizes the main functions of EphA2 and their relevance in bone sarcomas, providing strategies devised to leverage this receptor for diagnostic and therapeutic purposes, with a focus on its applicability in the three most common bone sarcoma histotypes: osteosarcoma, chondrosarcoma, and Ewing sarcoma.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182002","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}
Pub Date : 2024-09-09DOI: 10.1186/s12964-024-01819-z
Francesca Giammello, Chiara Biella, Erica Cecilia Priori, Matilde Amat Di San Filippo, Roberta Leone, Francesca D’Ambrosio, Martina Paterno’, Giulia Cassioli, Antea Minetti, Francesca Macchi, Cristina Spalletti, Ilaria Morella, Cristina Ruberti, Beatrice Tremonti, Federica Barbieri, Giuseppe Lombardi, Riccardo Brambilla, Tullio Florio, Rossella Galli, Paola Rossi, Federico Brandalise
Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle. We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo. We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav. This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment.
胶质母细胞瘤（GBM）是成人胶质瘤中发病率最高、侵袭性最强的一种。尽管采取了包括手术、放疗和化疗在内的强化治疗方法，但胶质母细胞瘤干细胞仍会导致肿瘤复发和预后不良。通过操纵转录机制诱导胶质母细胞瘤干细胞分化已成为治疗胶质母细胞瘤的一种有前途的策略。在这里，我们探索了一种创新方法，研究了在患者衍生的胶质母细胞瘤球形细胞（GSCs）中观察到的去极化静息膜电位（RMP）的作用，这种作用使它们能够在细胞周期的G0期保持干性特征。我们在体外和体内进行了分子生物学和电生理学实验，研究电压门控钠通道（Nav）在GSCs中的功能表达，尤其关注其依赖细胞周期的功能表达。研究人员对Nav的活性进行了药理调控，并通过活体成像细胞周期分析、自我更新实验和化学敏感性实验评估了Nav对GSCs行为的影响。我们通过体外通路分析和体内肿瘤增殖试验，研究了 Nav 在调控 GBM 干性中的作用机制。我们证明，Nav主要在细胞周期的G0期被GSCs功能性表达，这表明它在调节RMP中起着关键作用。通过诱导细胞周期从 G0 期重新进入 G1/S 过渡期，药物阻断 Nav 使 GBM 细胞更易受替莫唑胺（TMZ）的影响，而替莫唑胺是治疗这类肿瘤的标准药物。此外，抑制 Nav 能显著影响 GSCs 的自我更新和多能特征，同时提高它们的分化程度。最后，我们的数据表明，Nav通过使RMP去极化和抑制ERK信号通路来积极调节GBM干性。值得注意的是，体内增殖评估证实，药物阻断Nav后，患者对TMZ的敏感性增加。这一观点将Nav定位为一种有前景的预后生物标志物和GBM患者的治疗靶点，尤其是与替莫唑胺治疗结合使用时。
{"title":"Modulating voltage-gated sodium channels to enhance differentiation and sensitize glioblastoma cells to chemotherapy","authors":"Francesca Giammello, Chiara Biella, Erica Cecilia Priori, Matilde Amat Di San Filippo, Roberta Leone, Francesca D’Ambrosio, Martina Paterno’, Giulia Cassioli, Antea Minetti, Francesca Macchi, Cristina Spalletti, Ilaria Morella, Cristina Ruberti, Beatrice Tremonti, Federica Barbieri, Giuseppe Lombardi, Riccardo Brambilla, Tullio Florio, Rossella Galli, Paola Rossi, Federico Brandalise","doi":"10.1186/s12964-024-01819-z","DOIUrl":"https://doi.org/10.1186/s12964-024-01819-z","url":null,"abstract":"Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle. We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo. We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav. This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182001","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}
Pub Date : 2024-09-09DOI: 10.1186/s12964-024-01812-6
Ruijuan Liu, Yang Yu, Qingyang Wang, Qianxiang Zhao, Yan Yao, Mengxuan Sun, Jing Zhuang, Changgang Sun, Yuanfu Qi
Breast cancer ranks as one of the most common malignancies among women, with its prognosis and therapeutic efficacy heavily influenced by factors associated with the tumor cell biology, particularly the tumor microenvironment (TME). The diverse elements of the TME are engaged in dynamic bidirectional signaling interactions with various pathways, which together dictate the growth, invasiveness, and metastatic potential of breast cancer. The Hedgehog (Hh) signaling pathway, first identified in Drosophila, has been established as playing a critical role in human development and disease. Notably, the dysregulation of the Hh pathway is recognized as a major driver in the initiation, progression, and metastasis of breast cancer. Consequently, elucidating the mechanisms by which the Hh pathway interacts with the distinct components of the breast cancer TME is essential for comprehensively evaluating the link between Hh pathway activation and breast cancer risk. This understanding is also imperative for devising novel targeted therapeutic strategies and preventive measures against breast cancer. In this review, we delineate the current understanding of the impact of Hh pathway perturbations on the breast cancer TME, including the intricate and complex network of intersecting signaling cascades. Additionally, we focus on the therapeutic promise and clinical challenges of Hh pathway inhibitors that target the TME, providing insights into their potential clinical utility and the obstacles that must be overcome to harness their full therapeutic potential.
{"title":"Interactions between hedgehog signaling pathway and the complex tumor microenvironment in breast cancer: current knowledge and therapeutic promises","authors":"Ruijuan Liu, Yang Yu, Qingyang Wang, Qianxiang Zhao, Yan Yao, Mengxuan Sun, Jing Zhuang, Changgang Sun, Yuanfu Qi","doi":"10.1186/s12964-024-01812-6","DOIUrl":"https://doi.org/10.1186/s12964-024-01812-6","url":null,"abstract":"Breast cancer ranks as one of the most common malignancies among women, with its prognosis and therapeutic efficacy heavily influenced by factors associated with the tumor cell biology, particularly the tumor microenvironment (TME). The diverse elements of the TME are engaged in dynamic bidirectional signaling interactions with various pathways, which together dictate the growth, invasiveness, and metastatic potential of breast cancer. The Hedgehog (Hh) signaling pathway, first identified in Drosophila, has been established as playing a critical role in human development and disease. Notably, the dysregulation of the Hh pathway is recognized as a major driver in the initiation, progression, and metastasis of breast cancer. Consequently, elucidating the mechanisms by which the Hh pathway interacts with the distinct components of the breast cancer TME is essential for comprehensively evaluating the link between Hh pathway activation and breast cancer risk. This understanding is also imperative for devising novel targeted therapeutic strategies and preventive measures against breast cancer. In this review, we delineate the current understanding of the impact of Hh pathway perturbations on the breast cancer TME, including the intricate and complex network of intersecting signaling cascades. Additionally, we focus on the therapeutic promise and clinical challenges of Hh pathway inhibitors that target the TME, providing insights into their potential clinical utility and the obstacles that must be overcome to harness their full therapeutic potential.","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142182003","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}
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