{"title":"缺氧激活的CBS/H2S信号通过cd36介导的脂肪酸代谢驱动AML耐药","authors":"Qianpeng Li, Qin Li, Haifeng Han, Maowen Liu, Nannan Lyu, Zhiyuan Qiu, Rui Zhang, Xiaofeng Li, Xuehong Ran","doi":"10.1093/jleuko/qiaf065","DOIUrl":null,"url":null,"abstract":"<p><p>Hypoxia-associated hydrogen sulfide (H2S) accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which cystathionine β-synthase (CBS)/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-C-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-C-resistant AML cells was further scrutinized. sh-CBS or sh-thrombospondin 1 (THBS1) was transfected into ara-C-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, and lipid metabolism level were evaluated by the cell counting kit-8, flow cytometry, kit, and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and carnitine palmitoyltransferase-1α, as well as downregulated short-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor α levels, while these effects of hypoxia were all reversed by sh-CBS. sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through the mediation of THBS1 methylation.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hypoxia-activated cystathionine β-synthase/H2S signaling drives drug resistance in acute myeloid leukemia through CD36-mediated fatty acid metabolism.\",\"authors\":\"Qianpeng Li, Qin Li, Haifeng Han, Maowen Liu, Nannan Lyu, Zhiyuan Qiu, Rui Zhang, Xiaofeng Li, Xuehong Ran\",\"doi\":\"10.1093/jleuko/qiaf065\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hypoxia-associated hydrogen sulfide (H2S) accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which cystathionine β-synthase (CBS)/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-C-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-C-resistant AML cells was further scrutinized. sh-CBS or sh-thrombospondin 1 (THBS1) was transfected into ara-C-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, and lipid metabolism level were evaluated by the cell counting kit-8, flow cytometry, kit, and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and carnitine palmitoyltransferase-1α, as well as downregulated short-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor α levels, while these effects of hypoxia were all reversed by sh-CBS. sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through the mediation of THBS1 methylation.</p>\",\"PeriodicalId\":16186,\"journal\":{\"name\":\"Journal of Leukocyte Biology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-06-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Leukocyte Biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jleuko/qiaf065\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Leukocyte Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jleuko/qiaf065","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Hypoxia-activated cystathionine β-synthase/H2S signaling drives drug resistance in acute myeloid leukemia through CD36-mediated fatty acid metabolism.
Hypoxia-associated hydrogen sulfide (H2S) accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which cystathionine β-synthase (CBS)/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-C-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-C-resistant AML cells was further scrutinized. sh-CBS or sh-thrombospondin 1 (THBS1) was transfected into ara-C-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, and lipid metabolism level were evaluated by the cell counting kit-8, flow cytometry, kit, and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and carnitine palmitoyltransferase-1α, as well as downregulated short-chain acyl-CoA dehydrogenase and peroxisome proliferator-activated receptor α levels, while these effects of hypoxia were all reversed by sh-CBS. sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through the mediation of THBS1 methylation.
期刊介绍：
JLB is a peer-reviewed, academic journal published by the Society for Leukocyte Biology for its members and the community of immunobiologists. The journal publishes papers devoted to the exploration of the cellular and molecular biology of granulocytes, mononuclear phagocytes, lymphocytes, NK cells, and other cells involved in host physiology and defense/resistance against disease. Since all cells in the body can directly or indirectly contribute to the maintenance of the integrity of the organism and restoration of homeostasis through repair, JLB also considers articles involving epithelial, endothelial, fibroblastic, neural, and other somatic cell types participating in host defense. Studies covering pathophysiology, cell development, differentiation and trafficking; fundamental, translational and clinical immunology, inflammation, extracellular mediators and effector molecules; receptors, signal transduction and genes are considered relevant. Research articles and reviews that provide a novel understanding in any of these fields are given priority as well as technical advances related to leukocyte research methods.
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