首页 > 最新文献

Cell Death & Disease最新文献

英文 中文
Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment. 代谢守门员:利用肿瘤衍生代谢物优化肿瘤微环境中基于 T 细胞的免疫疗法疗效。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07122-6
Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui

The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.

肿瘤微环境(TME)协调着肿瘤细胞和免疫细胞之间复杂的相互作用,对免疫反应起着至关重要的调节作用。这篇综述深入探讨了代谢重编程在肿瘤微环境中的关键作用,强调了肿瘤衍生代谢物如何影响 T 淋巴细胞的功能和癌症免疫疗法的疗效。我们将重点放在这些代谢物的不同作用上,研究乳酸、脂类、氨基酸和其他生化信号如何不仅作为代谢副产物,而且作为调节剂抑制或增强 T 细胞介导的免疫力。通过整合最新研究成果,我们强调了这些代谢物在促进肿瘤进展和抑制免疫监视方面的双重影响。此外,我们还提出了针对代谢途径的创新治疗策略,以恢复 TME 内的免疫功能。本综述提供的见解为开发旨在提高肿瘤免疫疗法成功率的代谢干预措施铺平了道路,为精准医学治疗癌症带来了新的希望。
{"title":"Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.","authors":"Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui","doi":"10.1038/s41419-024-07122-6","DOIUrl":"10.1038/s41419-024-07122-6","url":null,"abstract":"<p><p>The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"775"},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice. Ptk6-/- 雄性小鼠小肠中琥珀酸诱导的 2 型免疫激活和分泌细胞生成受损。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07149-9
Katarina Vlajic, Wenjun Bie, Milica B Gilic, Angela L Tyner

Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to the SRC family of tyrosine kinases. It is expressed in epithelial linings and regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to all wild type and Ptk6-/- female mice, Ptk6-/- male mice do not activate innate immunity or upregulate differentiation of the tuft and goblet secretory cell lineages following succinate treatment. Mechanistically, we found that PTK6 regulates Il25 and Irag2, genes that are required for tuft cell effector functions and activation of type 2 innate immunity, in organoids derived from intestines of male but not female mice. In patients with Crohn's disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in contributing to sex differences in intestinal innate immunity and provide new insights into the regulation of IL-25.

蛋白酪氨酸激酶 6(PTK6)是一种细胞内酪氨酸激酶,与酪氨酸激酶 SRC 家族关系密切。它在上皮内衬中表达,调节肠上皮的再生和修复。对公开数据集的分析表明,当2型免疫激活时,Ptk6在簇细胞中上调。我们发现,干扰 Ptk6 会影响参与肠道免疫反应的基因表达。在雄性而非雌性小鼠体内施用琥珀酸(模拟感染并激活簇细胞)会发现先天性免疫反应的激活依赖于 PTK6。与所有野生型小鼠和Ptk6-/-雌性小鼠相反,Ptk6-/-雄性小鼠在琥珀酸处理后不会激活先天性免疫或上调簇细胞和上睑分泌细胞系的分化。从机理上讲,我们发现 PTK6 在雄性小鼠而非雌性小鼠的肠道器官组织中调控簇细胞效应功能和 2 型先天性免疫激活所需的基因 Il25 和 Irag2。在克罗恩病患者中,PTK6 在肠道非炎症区域的簇细胞中上调。这些数据强调了 PTK6 在肠道先天性免疫性别差异中的作用,并为 IL-25 的调控提供了新的见解。
{"title":"Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice.","authors":"Katarina Vlajic, Wenjun Bie, Milica B Gilic, Angela L Tyner","doi":"10.1038/s41419-024-07149-9","DOIUrl":"10.1038/s41419-024-07149-9","url":null,"abstract":"<p><p>Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to the SRC family of tyrosine kinases. It is expressed in epithelial linings and regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to all wild type and Ptk6-/- female mice, Ptk6-/- male mice do not activate innate immunity or upregulate differentiation of the tuft and goblet secretory cell lineages following succinate treatment. Mechanistically, we found that PTK6 regulates Il25 and Irag2, genes that are required for tuft cell effector functions and activation of type 2 innate immunity, in organoids derived from intestines of male but not female mice. In patients with Crohn's disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in contributing to sex differences in intestinal innate immunity and provide new insights into the regulation of IL-25.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"777"},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Miro2 sulfhydration by CBS/H2S promotes human trophoblast invasion and migration via regulating mitochondria dynamics. CBS/H2S的Miro2硫酸化作用通过调节线粒体动力学促进人类滋养细胞的侵袭和迁移。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-26 DOI: 10.1038/s41419-024-07167-7
Hao Feng, Zongxin Sun, Baoshi Han, Huitang Xia, Lumei Chen, Chunlei Tian, Suhua Yan, Yugen Shi, Jie Yin, Wengang Song, Peipei Gong, Shuanglian Wang, Yan Li

Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (H2S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H2S levels were lower in PE patients' plasma; H2S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H2S donor, 1 µM) promoted CBS/H2S translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/H2S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2C185/C504) were highly sulfhydrated by H2S. Knockdown Miro2 or double mutation of Miro2C185/C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H2S. The present study showed that human cytotrophoblast receives low dose H2S regulation; CBS/H2S sustained mitochondria functions via Miro2C185/C504 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.

细胞母细胞(CTB)迁移和侵入母体子宫肌层不足会导致妊娠相关并发症,如宫内生长受限(IUGR)和先兆子痫(PE)。我们以前曾发现硫化氢(H2S)能增强 CTB 的迁移,但却不知道其机制和病理生理意义。通过研究人体样本和细胞系,我们发现 PE 患者血浆中的 H2S 水平较低;H2S 合成酶胱硫醚 β-合成酶(CBS)在 PE 非绒毛膜浸润性滋养细胞中减少。GYY4137(H2S 供体,1 µM)可促进 CBS/H2S 转位至线粒体,保护线粒体功能,增强细胞侵袭和迁移。敲除 CBS 会阻碍上述功能的发挥,而 GYY4137 则能挽救这些功能,这表明 CBS/H2S 信号具有重要作用。线粒体动力学紊乱抑制了细胞的侵袭和迁移。线粒体 Rho GTPase 2(Miro2C185/C504)的 185 和 504 半胱氨酸被 H2S 高度硫水化。敲除Miro2或将Miro2C185/C504双突变为丝氨酸会使线粒体破碎,并抑制细胞的侵袭和迁移,而H2S则无法挽救。本研究表明,人类细胞母细胞接受低剂量 H2S 的调控;CBS/H2S 通过 Miro2C185/C504 的硫水化作用维持线粒体的功能,从而增强细胞母细胞的移动性。这些发现为细胞母细胞功能建立了新的调控途径,并为 IUGR 和 PE 提供了新的靶点。
{"title":"Miro2 sulfhydration by CBS/H<sub>2</sub>S promotes human trophoblast invasion and migration via regulating mitochondria dynamics.","authors":"Hao Feng, Zongxin Sun, Baoshi Han, Huitang Xia, Lumei Chen, Chunlei Tian, Suhua Yan, Yugen Shi, Jie Yin, Wengang Song, Peipei Gong, Shuanglian Wang, Yan Li","doi":"10.1038/s41419-024-07167-7","DOIUrl":"10.1038/s41419-024-07167-7","url":null,"abstract":"<p><p>Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (H<sub>2</sub>S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H<sub>2</sub>S levels were lower in PE patients' plasma; H<sub>2</sub>S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H<sub>2</sub>S donor, 1 µM) promoted CBS/H<sub>2</sub>S translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/H<sub>2</sub>S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2<sup>C185/C504</sup>) were highly sulfhydrated by H<sub>2</sub>S. Knockdown Miro2 or double mutation of Miro2<sup>C185</sup>/<sup>C504</sup> to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H<sub>2</sub>S. The present study showed that human cytotrophoblast receives low dose H<sub>2</sub>S regulation; CBS/H<sub>2</sub>S sustained mitochondria functions via Miro2<sup>C185/C504</sup> sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"776"},"PeriodicalIF":8.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma. 单碳介导的嘌呤合成是胶质母细胞瘤产生替莫唑胺耐药性的原因。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-25 DOI: 10.1038/s41419-024-07170-y
Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das

Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.

胶质母细胞瘤占成人原发性恶性脑肿瘤的近一半,尽管采取了积极的治疗标准,包括切除手术和辅助化疗,但复发仍是普遍现象,总体中位生存期仅为 14.6 个月。最近的研究揭示了客体突变作为代谢适应关键介质在癌症进展中的重要性。在之前的研究中,我们发现了表观遗传修饰因子 ID-1 在胶质母细胞瘤的替莫唑胺耐药性中的作用。在这里,我们发现 ID-1 介导的胶质母细胞瘤肿瘤发生伴随着一碳(1-C)介导的嘌呤从头合成的上调。ID-1 基因敲除会导致一碳代谢和嘌呤合成酶的表达显著减少。对初次发病和复发时的胶质母细胞瘤手术标本进行分析后发现,1-C嘌呤合成代谢酶在复发性胶质母细胞瘤中富集,其表达与肿瘤复发时间缩短相关。此外,我们还发现 1-C 代谢表型是胶质母细胞瘤细胞增殖能力和替莫唑胺耐药性的基础。补充外源性嘌呤可恢复 ID-1 缺乏细胞的增殖能力,而用 AICAR 抑制嘌呤合成可使对替莫唑胺耐药的胶质母细胞瘤细胞对替莫唑胺化疗敏感。我们的数据表明,在耐药胶质瘤细胞中观察到的代谢表型是胶质母细胞瘤的潜在治疗靶点。
{"title":"One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.","authors":"Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das","doi":"10.1038/s41419-024-07170-y","DOIUrl":"https://doi.org/10.1038/s41419-024-07170-y","url":null,"abstract":"<p><p>Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"774"},"PeriodicalIF":8.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retraction Note: Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma. 撤稿说明:伊德拉利西通过 AKT/FoxO3a 促进肝细胞癌中 Bim 依赖性凋亡。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-24 DOI: 10.1038/s41419-024-07162-y
Dan Yue, Xun Sun
{"title":"Retraction Note: Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma.","authors":"Dan Yue, Xun Sun","doi":"10.1038/s41419-024-07162-y","DOIUrl":"https://doi.org/10.1038/s41419-024-07162-y","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"773"},"PeriodicalIF":8.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease. mGluR5 细胞内活性增强导致尼曼皮克 C 型病的精神改变。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07158-8
Ana Toledano-Zaragoza, Violeta Enriquez-Zarralanga, Sara Naya-Forcano, Víctor Briz, Rocío Alfaro-Ruíz, Miguel Parra-Martínez, Daniel N Mitroi, Rafael Luján, José A Esteban, María Dolores Ledesma

Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1nmf164) we show aberrant mGluR5 lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR5 distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR5 was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1nmf164 hippocampal slices. mGluR-LTD was lower or higher in Npc1nmf164 slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR5 agonists, respectively. Oral treatment with the mGluR5 antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1nmf164 mice. Increased neuronal mGluR5 levels were found in an NPC patient. These results implicate mGluR5 alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.

尼曼-皮克病 C 型(NPC)是由胆固醇转运蛋白 NPC1 突变引起的,导致脂质在溶酶体内积聚和精神改变。我们利用一种 NPC 小鼠模型(Npc1nmf164)显示,在 NPC1 缺失的神经元中,mGluR5 溶酶体积累异常,质膜减少。这种表型是通过遗传和药物 NPC1 沉默诱导野生型(wt)神经元形成的。提取胆固醇可使 mGluR5 在 NPC1 缺失神经元中的分布正常化。在非膜渗透性或膜渗透性 mGluR5 激动剂的刺激下,Npc1nmf164 海马切片的 mGluR-LTD 分别低于或高于 wt 海马切片。口服 mGluR5 拮抗剂 2-氯-4-((2,5-二甲基-1-(4-(三氟甲氧基)苯基)-1H-咪唑-4-基)乙炔基)吡啶(CTEP)可减少 mGluR-LTD 并改善 Npc1nmf164 小鼠的精神异常。在一名鼻咽癌患者体内发现了神经元 mGluR5 水平的升高。这些结果表明,mGluR5的改变与鼻咽癌精神状况有关,并提供了一种新的治疗策略,或许能帮助这种毁灭性疾病的患者。
{"title":"Enhanced mGluR<sub>5</sub> intracellular activity causes psychiatric alterations in Niemann Pick type C disease.","authors":"Ana Toledano-Zaragoza, Violeta Enriquez-Zarralanga, Sara Naya-Forcano, Víctor Briz, Rocío Alfaro-Ruíz, Miguel Parra-Martínez, Daniel N Mitroi, Rafael Luján, José A Esteban, María Dolores Ledesma","doi":"10.1038/s41419-024-07158-8","DOIUrl":"https://doi.org/10.1038/s41419-024-07158-8","url":null,"abstract":"<p><p>Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1<sup>nmf164</sup>) we show aberrant mGluR<sub>5</sub> lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR<sub>5</sub> distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR<sub>5</sub> was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1<sup>nmf164</sup> hippocampal slices. mGluR-LTD was lower or higher in Npc1<sup>nmf164</sup> slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR<sub>5</sub> agonists, respectively. Oral treatment with the mGluR<sub>5</sub> antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1<sup>nmf164</sup> mice. Increased neuronal mGluR<sub>5</sub> levels were found in an NPC patient. These results implicate mGluR<sub>5</sub> alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"771"},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination. VASH2 通过增加微管蛋白的脱酪氨酸化,增强 KIF3C 介导的表皮生长因子受体-内体循环,从而促进肺鳞癌的侵袭性和化疗耐药性。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07155-x
Jing Wang, Pengpeng Liu, Rui Zhang, Biyuan Xing, Guidong Chen, Lei Han, Jinpu Yu

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.

肺鳞状细胞癌(LUSC)死亡率高,治疗方法少。化疗仍是肺鳞癌患者的主要治疗手段,但多种药物耐药性已成为各种癌症化疗失败的主要挑战。因此,针对 LUSC 患者的有效治疗策略是一个亟待解决的问题。我们发现血管抑制素-2(VASH2)是LUSC患者的预后生物标志物,VASH2通过增加α-微管蛋白的脱酪氨酸化促进了LUSC细胞的恶性生物学行为和化疗耐药性。高水平的脱酪氨酸化微管蛋白与患者的预后呈负相关。阻断VASH2的微管蛋白羧肽酶(TCP)活性可抑制异种移植肿瘤的生长,并提高紫杉醇在体内的治疗效果。研究结果表明,VASH2诱导的小管蛋白脱酪氨酸化的增加促进了驱动蛋白家族成员3C(KIF3C)与微管的结合,并增强了KIF3C依赖的表皮生长因子受体(EGFR)的内体再循环,从而导致PI3K/Akt/mTOR信号的延长激活。这项研究表明,VASH2不仅是LUSC的预后生物标志物,也是一个很有前景的治疗靶点,这为化疗与TCP抑制剂EpoY联合治疗LUSC患者提供了新的思路。
{"title":"VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination.","authors":"Jing Wang, Pengpeng Liu, Rui Zhang, Biyuan Xing, Guidong Chen, Lei Han, Jinpu Yu","doi":"10.1038/s41419-024-07155-x","DOIUrl":"https://doi.org/10.1038/s41419-024-07155-x","url":null,"abstract":"<p><p>Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"772"},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression. 肝细胞特异性 NR5A2 缺乏症可通过下调 ALDH1B1 的表达诱导热变态反应并加剧非酒精性脂肪性肝炎。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-23 DOI: 10.1038/s41419-024-07151-1
Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li

Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2HKO) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.

非酒精性脂肪性肝炎(NASH)是一种普遍存在的慢性疾病,但其确切的发病机制和有效的治疗方法却仍然难以捉摸。核受体 5 亚家族 A 组成员 2(NR5A2)是一种与肝脏胆固醇代谢密切相关的转录因子,但由于 NR5A2 在细胞系和动物模型中缺失会导致死亡,因此一直未能对其进行全面研究。为了阐明 NR5A2 在 NASH 中的作用,我们产生了 Nr5a2 的肝细胞特异性基因敲除小鼠(Nr5a2HKO),并在常规饮食条件下对其不同年龄组的肝脏形态进行了检测。此外,我们还建立了表达单倍体水平 NR5A2 的细胞系,并随后重新引入了 NR5A2 的各种异构体。在 Nr5a2HKO 小鼠的肝脏中,炎症和纤维化从幼年开始自发出现,与脂质积累无关。NR5A2缺陷细胞系发生了猝死,而不同异构体的NR5A2能逆转这种细胞死亡形式。我们的研究结果揭示了抑制 NR5A2 会引发热凋亡,这是一种促炎性细胞死亡模式,主要由活性氧(ROS)诱导的 NF-κB 通路激活介导。作为 NR5A2 的转录调控分子,醛脱氢酶 1 家族成员 B1(ALDH1B1)通过调节 ROS 水平参与热凋亡。总之,NR5A2 的不同异构体通过维持 ROS 的微调平衡对 NASH 发挥保肝作用,而这取决于 ALDH1B1 的活性。
{"title":"Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression.","authors":"Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li","doi":"10.1038/s41419-024-07151-1","DOIUrl":"10.1038/s41419-024-07151-1","url":null,"abstract":"<p><p>Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2<sup>HKO</sup>) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2<sup>HKO</sup> mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"770"},"PeriodicalIF":8.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis. β-catenin抑制的LKB1 Sumoylation修饰和脂肪酸代谢对肾脏纤维化至关重要
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-22 DOI: 10.1038/s41419-024-07154-y
Shuangqin Chen, Jiemei Li, Ye Liang, Meijia Zhang, Ziqi Qiu, Sirui Liu, HaoRan Wang, Ye Zhu, Shicong Song, Xiaotao Hou, Canzhen Liu, Qinyu Wu, Mingsheng Zhu, Weiwei Shen, Jinhua Miao, Fan Fan Hou, Youhua Liu, Cheng Wang, Lili Zhou

Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.

肝激酶 B1(LKB1)是一种控制细胞稳态的丝氨酸/苏氨酸激酶。在翻译后修饰中,苏木酰化对 LKB1 激活 5'- 磷酸腺苷(AMP)激活的蛋白激酶(AMPK)至关重要,而 AMPK 是能量代谢的关键调节因子。值得注意的是,AMPK 调节的脂肪酸代谢与维持正常肾功能密切相关。然而,LKB1 Sumoylation 的调控机制仍然难以捉摸。在这项研究中,我们证实了肾脏纤维化中臭名昭著的信号--β-catenin抑制了LKB1的Sumoylation,从而破坏了肾小管细胞中的脂肪酸氧化,引发了肾脏纤维化。从机理上讲,我们发现Sumo3是肾小管细胞中LKB1 Sumoylation的关键介质,而LKB1的转录受到β-catenin/转录因子4(TCF4)信号的抑制。过表达Sumo3(而非Sumo1或Sumo2)可恢复被β-catenin破坏的脂肪酸代谢,并延缓肾脏中的脂质积累和纤维化。在体内,有条件地敲除肾小管细胞中的β-catenin,可通过维持LKB1 Sumoylation和AMPK活化,有效地保护脂肪酸氧化和阻止脂质积累。此外,在单侧缺血再灌注小鼠中,Sumo3的异位表达能强烈抑制Wnt1加重的脂质积累和纤维化。在慢性肾脏病患者中,我们发现了 Sumo3 的表达缺失,而且与 LKB1 的抑制高度相关。这导致脂肪酸代谢紊乱和脂质积累,从而导致肾脏纤维化。总之,我们的研究揭示了脂肪酸代谢障碍的新机制,并为调控肾脏纤维化中的Sumo修饰提供了新的治疗靶点途径。
{"title":"β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis.","authors":"Shuangqin Chen, Jiemei Li, Ye Liang, Meijia Zhang, Ziqi Qiu, Sirui Liu, HaoRan Wang, Ye Zhu, Shicong Song, Xiaotao Hou, Canzhen Liu, Qinyu Wu, Mingsheng Zhu, Weiwei Shen, Jinhua Miao, Fan Fan Hou, Youhua Liu, Cheng Wang, Lili Zhou","doi":"10.1038/s41419-024-07154-y","DOIUrl":"10.1038/s41419-024-07154-y","url":null,"abstract":"<p><p>Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"769"},"PeriodicalIF":8.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1. MAT1A 激活糖酵解以促进 NSCLC 进展取决于 CCND1 的稳定。
IF 8.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-22 DOI: 10.1038/s41419-024-07113-7
Shengping Shen, Ruili Liu, Jiazheng Huang, Yingjia Sun, Qiang Tan, Qingquan Luo, Ruijun Liu

Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.

非小细胞肺癌(NSCLC)作为全球癌症相关死亡的主要原因,仍然令人担忧。在有关蛋氨酸腺苷转移酶1A(MAT1A)在癌症中的作用和机制的争论中,我们的研究揭示了它在非小细胞肺癌中的意义。利用TCGA数据库和免疫组化染色,我们系统分析了MAT1A在NSCLC中的表达,发现了其明显的上调。为了揭示其功能和机理基础,我们在 NSCLC 细胞系中稳定敲除了 MAT1A。我们的研究结果表明,抑制 MAT1A 的表达可有效抑制 NSCLC 细胞的增殖和迁移能力,同时增强细胞凋亡。从机理上讲,我们发现抑制 MAT1A 可通过 S 期激酶相关蛋白 2(SKP2)介导的泛素化加速细胞周期关键调控因子 CCND1 的降解。值得注意的是,CCND1是MAT1A的重要伙伴,共同协调NSCLC细胞中的糖代谢。这种错综复杂的相互作用表明,MAT1A 通过保护 CCND1 蛋白的稳定性和激活糖酵解途径来促进 NSCLC 的进展,从而维持肿瘤的发生。总之,我们的研究不仅确定了 MAT1A 是 NSCLC 患者不良生存率的预后标志物,还阐明了它对癌症进展的机理贡献。这些发现为开发旨在破坏 NSCLC 中有害的 MAT1A-CCND1 糖酵解轴的靶向疗法铺平了道路。
{"title":"MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1.","authors":"Shengping Shen, Ruili Liu, Jiazheng Huang, Yingjia Sun, Qiang Tan, Qingquan Luo, Ruijun Liu","doi":"10.1038/s41419-024-07113-7","DOIUrl":"10.1038/s41419-024-07113-7","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 10","pages":"768"},"PeriodicalIF":8.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Cell Death & Disease
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1