Anna Kasprzyk-Pawelec, Mingjun Tan, Raneen Rahhal, Alec McIntosh, Harvey R. Fernandez, Rami M. Mosaoa, Lei Jiang, Gray W. Pearson, Eric Glasgow, Jerry Vockley, Christopher Albanese, Maria Laura Avantaggiati
{"title":"Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53","authors":"Anna Kasprzyk-Pawelec, Mingjun Tan, Raneen Rahhal, Alec McIntosh, Harvey R. Fernandez, Rami M. Mosaoa, Lei Jiang, Gray W. Pearson, Eric Glasgow, Jerry Vockley, Christopher Albanese, Maria Laura Avantaggiati","doi":"10.1038/s41418-024-01428-w","DOIUrl":"https://doi.org/10.1038/s41418-024-01428-w","url":null,"abstract":"<p>Germline inactivating mutations of the <i>SLC25A1</i> gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which <i>SLC25A1</i> loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of <i>SLC25A1</i> deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both <i>Slc25a1</i> alleles results in alterations in the development of multiple organs, and in a severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG <i>via</i> a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD<sup>+</sup>, which trigger senescence. Replenishing the pool of NAD<sup>+</sup> or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity <i>via</i> RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887877","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}
{"title":"Temporal dissection of the roles of Atg4 and ESCRT in autophagosome formation in yeast","authors":"Hui Li, Jing-Zhen Song, Cheng-Wen He, Meng-Xi Xie, Zheng-Tan Zhang, You Zhou, Xin-Jing Li, Li Cui, Jing Zhu, Qingqiu Gong, Zhiping Xie","doi":"10.1038/s41418-024-01438-8","DOIUrl":"https://doi.org/10.1038/s41418-024-01438-8","url":null,"abstract":"<p>Autophagosomes are formed by the enlargement and sealing of phagophores. This is accompanied by the recruitment and release of autophagy-related (Atg) proteins that function therein. Presently, the relationship among factors that act after the initial emergence of the phagophore is unclear. The endosomal sorting complexes required for transport (ESCRT) machinery and Atg4 are known to function in phagophore sealing and Atg8 release, respectively. Here we show that biochemically, both Atg4 and ESCRT promoted phagophore sealing. Intriguingly, Atg4-mediated release of Atg8 from the phagophore promoted phagophore sealing even in the absence of ESCRT. This sealing activity could be reconstituted in vitro using cell lysate and purified Atg4. To elucidate the temporal relationship between Atg4 and ESCRT, we charted a timeline of the autophagosome formation cycle based on the trafficking of Atg proteins and mapped the actions of Atg4 and ESCRT to specific stages. The temporal impact of Atg4-mediated release of Atg8 from phagophore was mapped to the stage after the assembly of phagophore assembly site (PAS) scaffold and phosphatidylinositol-3-kinase (PtdIns-3-K) complex; its retardation only extended the duration of Atg8 release stage, leading to delayed phagophore sealing and accumulation of multiple phagophores. The impacts of ESCRT were mapped to two stages. In addition to promoting phagophore sealing, it also dictates whether PtdIns-3-K recruitment can occur by controlling Atg9 trafficking, thereby determining the incidence of autophagosome formation. Accordingly, ESCRT deficiency led to a combination of reduced autophagosome frequency and extended autophagosome formation duration, manifesting as reduced autophagic flux but normal apparent Atg8 puncta number. Our study thus identifies Atg4-mediated Atg8 shedding as a novel membrane scission mechanism and reveals a new early-stage role for ESCRT in autophagy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"281 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874551","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}
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}
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}
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}
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}
{"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}
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}
{"title":"Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma","authors":"Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng, Guangyan Wei, Yongsheng Li, Yuechen Liu, Yingjie Lai, Yizhi Zhan, Dehua Wu, Yuan Fang","doi":"10.1038/s41418-024-01409-z","DOIUrl":"https://doi.org/10.1038/s41418-024-01409-z","url":null,"abstract":"<p>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<sup>+</sup> 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.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"10 1","pages":""},"PeriodicalIF":12.4,"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}
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}
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