Cell Death and Differentiation最新文献

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Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis 抑制硫氧还蛋白还原酶1可使葡萄糖饥饿的胶质母细胞瘤细胞对二硫下垂敏感
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-23 DOI: 10.1038/s41418-024-01440-0
Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Zhiqiang Qiu, Yan Gao, Dongxiao Sun, Gabrielle Peruggia, Jessica Sallavanti, Wei Li
{"title":"Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis","authors":"Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Zhiqiang Qiu, Yan Gao, Dongxiao Sun, Gabrielle Peruggia, Jessica Sallavanti, Wei Li","doi":"10.1038/s41418-024-01440-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01440-0","url":null,"abstract":"<p>Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic strategy for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear. Here, we found that inhibiting thioredoxin reductase 1 (TrxR1), a key enzyme in the thioredoxin system, induces disulfidptosis in glioblastoma (GBM) cells. TrxR1 expression is elevated in GBM with activated transcriptional coactivator with PDZ-binding motif (TAZ) and correlates with poor prognosis. TrxR1 inhibitors induced GBM cell death that can be rescued by disulfide reducers but not by ROS scavengers or inhibitors of apoptosis, ferroptosis, or necroptosis. Glucose-starved cells, but not those deprived of oxygen or glutamine, increased TrxR1 expression in an NRF2-dependent manner and were more sensitive to TrxR1 inhibition-induced cell death. The dying cells initially exhibited highly dynamic lamellipodia, followed by actin cytoskeleton collapse. This process involved the accumulation of cytosolic peroxisomes and micropinocytic caveolae, as well as small gaps in the plasma membrane. Depletion of the WAVE complex component NCKAP1 partially rescued the cells, whereas Rac inhibition enhanced cell death. In an orthotopic xenograft GBM mouse model, TrxR1 depletion inhibited tumor growth and improved survival. Furthermore, cells undergoing TrxR1 inhibition exhibited features of immunogenic cell death. Therefore, this study suggests the potential of targeting TrxR1 as a therapeutic strategy in GBM.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state ABT-263的衰老作用与来自非衰老状态的癌细胞固有的凋亡依赖性有关
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-21 DOI: 10.1038/s41418-024-01439-7
Fleur Jochems, Chrysiida Baltira, Julie A. MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C. de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards
{"title":"Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state","authors":"Fleur Jochems, Chrysiida Baltira, Julie A. MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C. de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards","doi":"10.1038/s41418-024-01439-7","DOIUrl":"https://doi.org/10.1038/s41418-024-01439-7","url":null,"abstract":"<p>Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"5 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The scramblases VMP1 and TMEM41B are required for primitive endoderm specification by targeting WNT signaling 超扰酶VMP1和TMEM41B是通过靶向WNT信号来实现原始内胚层规范所必需的
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-18 DOI: 10.1038/s41418-024-01435-x
Markus Holzner, Tea Sonicki, Hugo Hunn, Federico Uliana, Weijun Jiang, Vamshidhar R. Gade, Karsten Weis, Anton Wutz, Giulio Di Minin
{"title":"The scramblases VMP1 and TMEM41B are required for primitive endoderm specification by targeting WNT signaling","authors":"Markus Holzner, Tea Sonicki, Hugo Hunn, Federico Uliana, Weijun Jiang, Vamshidhar R. Gade, Karsten Weis, Anton Wutz, Giulio Di Minin","doi":"10.1038/s41418-024-01435-x","DOIUrl":"https://doi.org/10.1038/s41418-024-01435-x","url":null,"abstract":"<p>The ER-resident proteins VMP1 and TMEM41B share a conserved DedA domain, which confers lipid scramblase activity. Loss of either gene results in embryonic lethality in mice and defects in autophagy and lipid droplet metabolism. To investigate their role in pluripotency and lineage specification, we generated Vmp1 and Tmem41b mutations in mouse embryonic stem cells (ESCs). We observed that ESCs carrying mutations in Vmp1 and Tmem41b show robust self-renewal and an unperturbed pluripotent expression profile but accumulate LC3-positive autophagosomes and lipid droplets consistent with defects in autophagy and lipid metabolism. ESCs carrying combined mutations in Vmp1 and Tmem41b can differentiate into a wide range of embryonic cell types. However, differentiation into primitive endoderm-like cells in culture is impaired, and the establishment of extra-embryonic endoderm stem (XEN) cells is delayed. Mechanistically, we show the deregulation of genes that are associated with WNT signaling. This is further confirmed by cell surface proteome profiling, which identified a significant reduction of the WNT-receptor FZD2 at the plasma membrane in Vmp1 and Tmem41b double mutant ESCs. Importantly, we show that transgenic expression of Fzd2 rescues XEN differentiation. Our findings identify the role of the lipid scramblases VMP1 and TMEM41B in WNT signaling during extra-embryonic endoderm development and characterize their distinct and overlapping functions.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"66 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A STT3A-dependent PD-L1 glycosylation modification mediated by GMPS drives tumor immune evasion in hepatocellular carcinoma 由 GMPS 介导的 STT3A 依赖性 PD-L1 糖基化修饰驱动肝细胞癌中的肿瘤免疫逃避
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-17 DOI: 10.1038/s41418-024-01432-0
Xinyu Guo, Tianming Cui, Linmao Sun, Yumin Fu, Cheng Cheng, Chenghui Wu, Yitong Zhu, Shuhang Liang, Yufeng Liu, Shuo Zhou, Xianying Li, Changyong Ji, Kun Ma, Ning Zhang, Qi Chu, Changjian Xing, Shumin Deng, Jiabei Wang, Yao Liu, Lianxin Liu
{"title":"A STT3A-dependent PD-L1 glycosylation modification mediated by GMPS drives tumor immune evasion in hepatocellular carcinoma","authors":"Xinyu Guo, Tianming Cui, Linmao Sun, Yumin Fu, Cheng Cheng, Chenghui Wu, Yitong Zhu, Shuhang Liang, Yufeng Liu, Shuo Zhou, Xianying Li, Changyong Ji, Kun Ma, Ning Zhang, Qi Chu, Changjian Xing, Shumin Deng, Jiabei Wang, Yao Liu, Lianxin Liu","doi":"10.1038/s41418-024-01432-0","DOIUrl":"https://doi.org/10.1038/s41418-024-01432-0","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a malignant tumor characterized by rapid progression. To explore the regulatory mechanism of rapid tumor growth and metastasis, we conducted proteomic and scRNA-Seq analyses on advanced HCC tissues and identified a significant molecule, guanine monophosphate synthase (GMPS), closely associated with the immune evasion in HCC. We analyzed the immune microenvironment characteristics remodeled by GMPS using scRNA-Seq and found GMPS induced tumor immune evasion in HCC by impairing the tumor-killing function of CD8 <sup>+</sup> T cells. Further investigation revealed that GMPS increased PD-L1 expression by regulating its ubiquitination and glycosylation modification. Mechanistically, GMPS enhanced the bond between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST) by acting as an additional module connecting the Sec61 channel complex and STT3A, which aided in the translocation and modification of nascent peptides. Increased PD-L1 impaired the tumor-killing function of CD8 <sup>+</sup> T cells, leading to the immune evasion. Importantly, targeting GMPS with angustmycin A, an inhibitor of GMPS activity, significantly suppressed PD-L1 expression and tumor growth in HCC, which also increased the sensitivity to anti-CTLA-4 immunotherapy. These findings suggested the potential of targeting GMPS as a promising therapeutic approach for HCC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"30 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis 蛋氨酸驱动的YTHDF1表达通过减弱rig - i调节的免疫反应和增强eIF5B-PD-L1轴促进膀胱癌的进展
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-13 DOI: 10.1038/s41418-024-01434-y
Anze Yu, Liangmin Fu, Lanyu Jing, Yinghan Wang, Zifang Ma, Xinwei Zhou, Rui Yang, Jinhui Liu, Jiao Hu, Wei Feng, Taowei Yang, Zhenhua Chen, Xiongbing Zu, Wei Chen, Junxing Chen, Junhang Luo
{"title":"Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis","authors":"Anze Yu, Liangmin Fu, Lanyu Jing, Yinghan Wang, Zifang Ma, Xinwei Zhou, Rui Yang, Jinhui Liu, Jiao Hu, Wei Feng, Taowei Yang, Zhenhua Chen, Xiongbing Zu, Wei Chen, Junxing Chen, Junhang Luo","doi":"10.1038/s41418-024-01434-y","DOIUrl":"https://doi.org/10.1038/s41418-024-01434-y","url":null,"abstract":"<p>The impact of amino acids on tumor immunotherapy is gradually being uncovered. In this study, we screened various essential and non-essential amino acids and found that methionine enhances mRNA methylation and reduced the activation of Type I interferon pathway in bladder cancer. Through RNA sequencing, point mutations, MB49 mouse tumor models, and single-cell RNA sequencing, we demonstrated that high methionine levels elevate the expression of m<sup>6</sup>A reader YTHDF1, promoting the degradation of RIG-I, thereby inhibiting the RIG-I/MAVS-mediated IFN-I pathway and reducing the efficacy of tumor immunotherapy. Additionally, immunoprecipitation and mass spectrometry revealed that YTHDF1 binds to the eukaryotic translation initiation factor eIF5B, which acts on PD-L1 mRNA to enhance its translation and promote immune evasion. By intravesical administration of oncolytic bacteria VNP20009, we effectively depleted methionine locally, significantly prolonging mouse survival and enhancing immune cell infiltration and differentiation within tumors. Multiplex immunofluorescence assays in bladder cancer immunotherapy patients confirmed our findings. Our research elucidates two mechanisms by which methionine inhibits bladder cancer immunotherapy and proposes a targeted methionine depletion strategy that advances research while minimizing nutritional impact on patients.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"117 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma AT2细胞中Fbxo45的缺失导致组蛋白供应不足并引发肺腺癌
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-13 DOI: 10.1038/s41418-024-01433-z
Lian Li, Junya Li, Ran Chen, Caihu Huang, Yong Zuo, Runhui Lu, Xiaojia Liu, Jiayi Huang, Yanli Wang, Xian Zhao, Jinke Cheng, Xiaojing Zhao, Chunling Du, Jianxiu Yu
{"title":"Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma","authors":"Lian Li, Junya Li, Ran Chen, Caihu Huang, Yong Zuo, Runhui Lu, Xiaojia Liu, Jiayi Huang, Yanli Wang, Xian Zhao, Jinke Cheng, Xiaojing Zhao, Chunling Du, Jianxiu Yu","doi":"10.1038/s41418-024-01433-z","DOIUrl":"https://doi.org/10.1038/s41418-024-01433-z","url":null,"abstract":"<p>Dysregulation of histone supply is implicated in various cancers, including lung adenocarcinoma (LUAD), although the underlying mechanisms remain poorly understood. Here, we demonstrate that knockout of Fbxo45 in mouse alveolar epithelial type 2 (AT2) cells leads to spontaneous LUAD. Our findings reveal that FBXO45 is a novel cell-cycle-regulated protein that is degraded upon phosphorylation by CDK1 during the S/G2 phase. During the S phase or DNA damage repair, FBXO45 binds to UPF1 and recruits the phosphatase PPP6C, thereby inhibiting UPF1 phosphorylation. This process is crucial for preventing the degradation of replication-dependent (RD) histone mRNAs and ensuring an adequate histone supply. In the absence of FBXO45, the impaired interaction between PPP6C and UPF1 results in sustained hyperphosphorylation of UPF1 throughout the cell cycle, leading to an insufficient histone supply, chromatin relaxation, genomic instability, and an increased rate of gene mutations, ultimately culminating in malignant transformation. Notably, analysis of clinical LUAD specimens confirms a positive correlation between the loss of FBXO45 and genomic instability, which is consistent with our findings in the mouse model. These results highlight the critical role of FBXO45 as a genomic guardian in coordinating histone supply and DNA replication, providing valuable insights into potential therapeutic targets and strategies for the treatment of LUAD.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"82 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma 精胺合酶参与肝细胞癌巨噬细胞M2极化破坏抗肿瘤免疫
IF 13.7 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-10 DOI: 10.1038/s41418-024-01409-z
Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng, Guangyan Wei, Yongsheng Li, Yuechen Liu, Yingjie Lai, Yizhi Zhan, Dehua Wu, Yuan Fang
{"title":"Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma","authors":"Yining Sun,&nbsp;Peitao Zhou,&nbsp;Junying Qian,&nbsp;Qin Zeng,&nbsp;Guangyan Wei,&nbsp;Yongsheng Li,&nbsp;Yuechen Liu,&nbsp;Yingjie Lai,&nbsp;Yizhi Zhan,&nbsp;Dehua Wu,&nbsp;Yuan Fang","doi":"10.1038/s41418-024-01409-z","DOIUrl":"10.1038/s41418-024-01409-z","url":null,"abstract":"Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via “subcutaneous” and “orthotopic” HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 3","pages":"573-586"},"PeriodicalIF":13.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer 乳酸脱氢酶B在kras驱动的肺癌中非典型地促进铁下垂防御
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-07 DOI: 10.1038/s41418-024-01427-x
Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Zhang Yang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A. Schmid, Thomas M. Marti, Patrick Dorn, Ren-Wang Peng
{"title":"Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer","authors":"Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Zhang Yang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A. Schmid, Thomas M. Marti, Patrick Dorn, Ren-Wang Peng","doi":"10.1038/s41418-024-01427-x","DOIUrl":"https://doi.org/10.1038/s41418-024-01427-x","url":null,"abstract":"<p>Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in <i>KRAS</i>-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing <i>KRAS</i>-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat <i>KRAS</i>-driven lung cancer.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401. 更正:EGFR通过磷酸化TNFR1酪氨酸360和401抑制TNF-α介导的途径。
IF 13.7 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-03 DOI: 10.1038/s41418-024-01425-z
Young Woo Nam, June-Ha Shin, Seongmi Kim, Chi Hyun Hwang, Choong-Sil Lee, Gyuho Hwang, Hwa-Ryeon Kim, Jae-Seok Roe, Jaewhan Song
{"title":"Correction: EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401.","authors":"Young Woo Nam, June-Ha Shin, Seongmi Kim, Chi Hyun Hwang, Choong-Sil Lee, Gyuho Hwang, Hwa-Ryeon Kim, Jae-Seok Roe, Jaewhan Song","doi":"10.1038/s41418-024-01425-z","DOIUrl":"https://doi.org/10.1038/s41418-024-01425-z","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer 在胰腺癌中,USP19通过去泛素化NEK9抑制mTOR通路,从而增强自噬细胞死亡
IF 12.4 1区 生物学
Cell Death and Differentiation Pub Date : 2024-12-03 DOI: 10.1038/s41418-024-01426-y
Guangfu Wang, Shangnan Dai, Jin Chen, Kai Zhang, Chenyu Huang, Jinfan Zhang, Kunxin Xie, Fuye Lin, Huijuan Wang, Yong Gao, Lingdi Yin, Kuirong Jiang, Yi Miao, Zipeng Lu
{"title":"USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer","authors":"Guangfu Wang, Shangnan Dai, Jin Chen, Kai Zhang, Chenyu Huang, Jinfan Zhang, Kunxin Xie, Fuye Lin, Huijuan Wang, Yong Gao, Lingdi Yin, Kuirong Jiang, Yi Miao, Zipeng Lu","doi":"10.1038/s41418-024-01426-y","DOIUrl":"https://doi.org/10.1038/s41418-024-01426-y","url":null,"abstract":"<p>The ubiquitin-specific protease (USP) family is the largest and most diverse deubiquitinase (DUBs) family and plays a significant role in maintaining cell homeostasis. Dysregulation of USPs has been associated with carcinogenesis of various tumors. We identified that USP19 was downregulated in pancreatic tumor tissues and forced expression of USP19 diminished tumorigenicity of pancreatic cancer. Mechanistically, USP19 directly interacts with and stabilized NEK9 via inhibiting K48-specific polyubiquitination process on NEK9 protein at K525 site through its USP domain. Moreover, NEK9 phosphorylates the regulatory associated protein of mTOR (Raptor) at Ser792 and links USP19 to the inhibition of mTORC1 signaling pathway, which further leads to autophagic cell death of pancreatic cancer cells. Inhibition of autophagy by Atg5 knockdown or lysosome inhibitor bafilomycin A1 abolished the decreased malignant phenotype of USP19- and NEK9-overexpressing cancer cells. Importantly, USP19 expression exhibits a positive correlation with NEK9 expression in clinical samples, and low USP19 or NEK9 expression is associated with a worse prognosis. This study revealed that USP19-mediated NEK9 deubiquitylation is a regulatory mechanism for mTORC1 inhibition and provides a therapeutic target for diseases involving mTORC1 dysregulation.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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