Pub Date : 2024-10-26DOI: 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}
Pub Date : 2024-10-26DOI: 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.
{"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}
Pub Date : 2024-10-26DOI: 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}
Pub Date : 2024-10-25DOI: 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.
{"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}
Pub Date : 2024-10-23DOI: 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.
{"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}
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.
{"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}
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.
{"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}
Pub Date : 2024-10-22DOI: 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.
{"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}
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.
{"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}