Heart failure is associated with myocardial fibrosis,a pivotal histopathological feature arising from β-adrenergic receptor(β-AR) stimulation through sympathetic nervous system activation.Augmented glutaminolysis wi...Heart failure is associated with myocardial fibrosis,a pivotal histopathological feature arising from β-adrenergic receptor(β-AR) stimulation through sympathetic nervous system activation.Augmented glutaminolysis with increased bioavailability of α-ketoglutarate(α-KG) is suggested to contribute to fibrogenesis and changes in cellular gene expression.K_(Ca)3.1 is a calcium-activated potassium channel expressed in fibroblasts and has been implicated in mediating fibrosis,yet the putative interactions between glutaminolysis and K_(Ca)3.1 in β-ARmediated cardiac fibrosis remain poorly understood.Here,we performed a series of in vitro and in vivo experiments to investigate how α-KG might influence the expression of K_(Ca)3.1 in the context of experimental myocardial fibrosis driven by β-AR activation.In cultured adult mouse cardiac fibroblasts,α-KG exposure resulted in the upregulation of K_(Ca)3.1 m RNA and protein levels that were commensurate with the dose and duration of exposure,and also led to increased K_(Ca)3.1 channel currents.Exposure to α-KG led to a significant decrease in levels of histone methylation(H3K27me3) within the K_(Ca)3.1 promoter,a decrease in the association of the transcription repressor REST from this site,as well as an enrichment of transcription activator AP-1 binding.The exacerbated fibrotic signaling induced by α-KG in cultured fibroblasts was suppressed by functional inhibition of K_(Ca)3.1 or by genetic knockdown of Kcnn4.Moreover,β-AR activation by isoproterenol significantly augmented glutaminolysis mediated by glutaminase 1(GLS1) and significantly increased α-KG levels detected in the supernatant of cultured fibroblasts and cardiomyocytes.In addition,isoproterenol-induced K_(Ca)3.1 expression in fibroblasts was curtailed by treatment with the GLS1 inhibitor CB-839,or by GLS1 gene knockdown,or by treatment with the selective β_2-AR antagonist,ICI118551.In mouse models of established cardiac fibrosis evoked by isoproterenol-stimulation or β_2-AR overexpression,treatment with CB-839 for 4 weeks suppressed the phenotypic features of fibrosis,and this was associated with a decline in α-KG tissue content,a lack of histone demethylation at the K_(Ca)3.1 promoter,as well as suppression of K_(Ca)3.1 expression.Taken together,our study demonstrates for the first time that glutaminolysis contributes to β-AR activation-induced myocardial fibrosis via α-KG-stimulated K_(Ca)3.1 expression.We anticipate that treatments which target the β-AR/GLS1/α-KG/K_(Ca)3.1 signaling pathway might be effective for cardiac fibrosis.展开更多
Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interven...Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.展开更多
Aim:This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma(MM)despite significant therapeutic advances and the introduction of novel agents.Our study focused on how ...Aim:This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma(MM)despite significant therapeutic advances and the introduction of novel agents.Our study focused on how myeloma cells mediate the metabolic pathways essential for survival.Therefore,we examined the role of glutaminolysis in this process.Methods:We investigated the role of glutaminolysis in myeloma cell growth.In addition,we analyzed the ability of CB-839(telaglenastat),a glutaminase(GLS)inhibitor,to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase(HDAC)inhibitors.Results:Glutamate deprivation significantly reduced MM cell proliferation.We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls.CB-839 inhibits MM cell proliferation in a dose-dependent manner,resulting in enhanced cytotoxicity.Additionally,intracellularα-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration.Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity.Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results.Compared to control cells,these cells also showed increased sensitivity to panobinostat.Conclusion:Glutaminolysis contributes to the viability of MM cells,and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition.These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.展开更多
Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistan...Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warhurg＇s discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.展开更多
Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are le...Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.展开更多
Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic a...Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support.Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME,also rely on glutaminolysis as the“engine”of angiogenesis.Additionally,the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well.Herein,we developed a type of siRNA micelleplexes(MH@siGLS1)to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization-and TAMs repolarization-enhanced photo-immunotherapy.Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy,which was available to trigger immunogenic cell death for adaptive antitumor immune responses.Meanwhile,glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification.This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.展开更多
The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells by...The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.展开更多
Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and impro...Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment.Here,we show that carboxyamidotriazole(CAI),an anticancer drug,can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism.CAI suppressed glucose and lipid metabolism utilization,causing inhibition of mitochondrial respiratory chain complex I,thus producing reactive oxygen species(ROS).In parallel,activation of the aryl hydrocarbon receptor(Ah R)increased glutamine uptake via the transporter SLC1A5,which could activate the ROS-scavenging enzyme glutathione peroxidase.As a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy metabolism.These data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.展开更多
The primary features of cancer are maintained via intrinsically modified metabolic activity, which is characterized by enhanced nutrient supply, energy production, and biosynthetic activity to synthesize a variety of ...The primary features of cancer are maintained via intrinsically modified metabolic activity, which is characterized by enhanced nutrient supply, energy production, and biosynthetic activity to synthesize a variety of macromolecular components during each passage through the cell cycle. This metabolic shift in transformed cells, as compared with non-proliferating cells, in-volves aberrant activation of aerobic glycolysis, de novo lipid biosynthesis and glutamine-dependent anaplerosis to fuel robust cell growth and proliferation. Here, we discuss the unique metabolic characteristics of cancer, the constitutive regulation of metabolism through a variety of signal transduction pathways and/or enzymes involved in metabolic reprogramming in cancer cells, and their implications in cancer diagnosis and therapy.展开更多
Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by re...Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.展开更多
基金supported by the National Natural Science Foundation of China (82170298,82070393,32171103,82270327)。
文摘Heart failure is associated with myocardial fibrosis,a pivotal histopathological feature arising from β-adrenergic receptor(β-AR) stimulation through sympathetic nervous system activation.Augmented glutaminolysis with increased bioavailability of α-ketoglutarate(α-KG) is suggested to contribute to fibrogenesis and changes in cellular gene expression.K_(Ca)3.1 is a calcium-activated potassium channel expressed in fibroblasts and has been implicated in mediating fibrosis,yet the putative interactions between glutaminolysis and K_(Ca)3.1 in β-ARmediated cardiac fibrosis remain poorly understood.Here,we performed a series of in vitro and in vivo experiments to investigate how α-KG might influence the expression of K_(Ca)3.1 in the context of experimental myocardial fibrosis driven by β-AR activation.In cultured adult mouse cardiac fibroblasts,α-KG exposure resulted in the upregulation of K_(Ca)3.1 m RNA and protein levels that were commensurate with the dose and duration of exposure,and also led to increased K_(Ca)3.1 channel currents.Exposure to α-KG led to a significant decrease in levels of histone methylation(H3K27me3) within the K_(Ca)3.1 promoter,a decrease in the association of the transcription repressor REST from this site,as well as an enrichment of transcription activator AP-1 binding.The exacerbated fibrotic signaling induced by α-KG in cultured fibroblasts was suppressed by functional inhibition of K_(Ca)3.1 or by genetic knockdown of Kcnn4.Moreover,β-AR activation by isoproterenol significantly augmented glutaminolysis mediated by glutaminase 1(GLS1) and significantly increased α-KG levels detected in the supernatant of cultured fibroblasts and cardiomyocytes.In addition,isoproterenol-induced K_(Ca)3.1 expression in fibroblasts was curtailed by treatment with the GLS1 inhibitor CB-839,or by GLS1 gene knockdown,or by treatment with the selective β_2-AR antagonist,ICI118551.In mouse models of established cardiac fibrosis evoked by isoproterenol-stimulation or β_2-AR overexpression,treatment with CB-839 for 4 weeks suppressed the phenotypic features of fibrosis,and this was associated with a decline in α-KG tissue content,a lack of histone demethylation at the K_(Ca)3.1 promoter,as well as suppression of K_(Ca)3.1 expression.Taken together,our study demonstrates for the first time that glutaminolysis contributes to β-AR activation-induced myocardial fibrosis via α-KG-stimulated K_(Ca)3.1 expression.We anticipate that treatments which target the β-AR/GLS1/α-KG/K_(Ca)3.1 signaling pathway might be effective for cardiac fibrosis.
基金supported in part by the Moonshot Research and Development Program(Grant No.21zf0127003h001,Japan)JSPS A3 Foresight Program(Grant No.JPJSA3F20230001,Japan)JSPS KAKENHI(Grants No.23H02867,23H05487,and 21K07659,Japan).
文摘Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.
基金approved by the Ethics Committee of Tokyo Medical University(No.T2023-0105).
文摘Aim:This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma(MM)despite significant therapeutic advances and the introduction of novel agents.Our study focused on how myeloma cells mediate the metabolic pathways essential for survival.Therefore,we examined the role of glutaminolysis in this process.Methods:We investigated the role of glutaminolysis in myeloma cell growth.In addition,we analyzed the ability of CB-839(telaglenastat),a glutaminase(GLS)inhibitor,to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase(HDAC)inhibitors.Results:Glutamate deprivation significantly reduced MM cell proliferation.We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls.CB-839 inhibits MM cell proliferation in a dose-dependent manner,resulting in enhanced cytotoxicity.Additionally,intracellularα-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration.Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity.Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results.Compared to control cells,these cells also showed increased sensitivity to panobinostat.Conclusion:Glutaminolysis contributes to the viability of MM cells,and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition.These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.
基金supported by the National Institutes of Health through The University of Texas MD Anderson Cancer Center’s Support Grant CA016672National Cancer Institute grant RO1CA 089266 (MHL)+3 种基金Directed Medical Research Programs Department of Defense Synergistic Idea Development Award BC062166 (SCY, MHL)the Susan G.Komen Breast Cancer Research Foundation Promise Grant KG081048 (SCY, MHL)Vietnam Education Foundation, Rosalie B.Hite FoundationDepartment of Defense Breast Cancer Research Program (Award # W81XWH-10-0171)
文摘Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warhurg＇s discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.
文摘Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.
基金National Key Research and Development Program of China(2023YFD1800105)National Natural Science Foundation of China(32322043,32171313,and 82272154)+4 种基金Tianjin Science Fund for Distinguished Young Scholars(22JCJQJC00120,China)Shenzhen Science and Technology Program(RCYX20210706092104033,and JCYJ20210324124402006,China)the Fundamental Research Funds for the Central Universities(2021-RC310-005,China)Science and Technology Program of Tianjin City(the Basic Research Cooperation Special Foundation of Beijing-Tianjin-Hebei Region,22JCZXJC00060,China)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2024-I2M-TS-028,2021-I2M-5-012,2021-I2M-1-058,and 2022-I2M-2-003,China).
文摘Among tumor microenvironment(TME),the entire metabolic characteristics of tumorresident cells are reprogrammed to benefit the expansion of tumor cells,which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support.Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME,also rely on glutaminolysis as the“engine”of angiogenesis.Additionally,the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well.Herein,we developed a type of siRNA micelleplexes(MH@siGLS1)to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization-and TAMs repolarization-enhanced photo-immunotherapy.Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy,which was available to trigger immunogenic cell death for adaptive antitumor immune responses.Meanwhile,glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification.This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.
文摘The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.
基金supported by the National Natural Science Foundation of China(grants 81872897 and 81672966)the CAMS Major Collaborative Innovation Project 2016-I2 M-1-011(China)。
文摘Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment.Here,we show that carboxyamidotriazole(CAI),an anticancer drug,can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism.CAI suppressed glucose and lipid metabolism utilization,causing inhibition of mitochondrial respiratory chain complex I,thus producing reactive oxygen species(ROS).In parallel,activation of the aryl hydrocarbon receptor(Ah R)increased glutamine uptake via the transporter SLC1A5,which could activate the ROS-scavenging enzyme glutathione peroxidase.As a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy metabolism.These data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.
基金supported by the National Basic Research Program of Chi-na (Grant No. 2011CB910703)the National High-Tech Research and Development Program of China (Grant No. 2007AA021205)
文摘The primary features of cancer are maintained via intrinsically modified metabolic activity, which is characterized by enhanced nutrient supply, energy production, and biosynthetic activity to synthesize a variety of macromolecular components during each passage through the cell cycle. This metabolic shift in transformed cells, as compared with non-proliferating cells, in-volves aberrant activation of aerobic glycolysis, de novo lipid biosynthesis and glutamine-dependent anaplerosis to fuel robust cell growth and proliferation. Here, we discuss the unique metabolic characteristics of cancer, the constitutive regulation of metabolism through a variety of signal transduction pathways and/or enzymes involved in metabolic reprogramming in cancer cells, and their implications in cancer diagnosis and therapy.
基金supported by Japan Society for the Promotion of Science,Japan(Grant Number:23K08806).
文摘Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.
