Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells. Upregulated aerobic glycolysis(Warburg effect) in gastric cancer meeting the demands of cell proliferation is associated with ge...Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells. Upregulated aerobic glycolysis(Warburg effect) in gastric cancer meeting the demands of cell proliferation is associated with genetic mutations, epigenetic modification and proteomic alteration. Understanding the mechanisms of aerobic glycolysis may contribute to our knowledge of gastric carcinogenesis. Metabolomic studies offer novel, convenient and practical tools in the search for new biomarkers for early detection, diagnosis, prognosis, and chemosensitivity prediction of gastric cancer. Interfering with the process of glycolysis in cancer cells may provide a new and promising therapeutic strategy for gastric cancer. In this article, we present a brief review of recent studies of glucose metabolism in gastric cancer, with primary focus on the clinical applications of new biomarkers and their potential therapeutic role in gastric cancer.展开更多
Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the opti...Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.展开更多
Pyruvate kinase isoform M2 （PKM2） converts phospho- enolpyruvate （PEP） to pyruvate and plays an important role in cancer metabolism. Here, we show that post- translational modifications and a patient-derived muta-...Pyruvate kinase isoform M2 （PKM2） converts phospho- enolpyruvate （PEP） to pyruvate and plays an important role in cancer metabolism. Here, we show that post- translational modifications and a patient-derived muta- tion regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a ＂seesaw＂ model to illustrate confor- mational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2^Y105E （phos- phorylation mimic of Y105） decreases pyruvate kinase activity by inhibiting FBP （fructose 1,6-bisphosphate）- induced R-state formation, and PKM2K^3305Q （acetylation mimic of K305） abolishes the activity by hindering tet- ramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post- translational modifications and a patient-derived muta- tion and provides a structural basis for further investi- gation of other modifications and mutations of PKM2 yet to be discovered.展开更多
Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival,proliferation and the ability to perform specific and functional immune responses within the tumor mi...Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival,proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment.A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer treatments.Toll-like receptors(TLRs)have recently been recognized as critical factors involved in tumor pathogenesis,regulating both tumor cells and tumor-infiltrating innate and adaptive immune cells.However,little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism,although there is abundant expression of TLRs in these cells.In this review,we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor microenvironment.In particular,we discuss how malignant tumors regulate metabolism to support their growth and survival,summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells,and further explore potential strategies targeting cell metabolism for TLR-based cancer therapy.An improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.展开更多
Objective:Upper gastrointestinal(UGI)cancers,predominantly gastric cancer(GC)and esophageal cancer(EC),are malignant tumor types with high morbidity and mortality rates.Accumulating studies have focused on metabolomic...Objective:Upper gastrointestinal(UGI)cancers,predominantly gastric cancer(GC)and esophageal cancer(EC),are malignant tumor types with high morbidity and mortality rates.Accumulating studies have focused on metabolomic profiling of UGI cancers in recent years.In this systematic review,we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with GC and EC.Methods:A systematic search of three databases(Embase,PubMed,and Web of Science)for molecular epidemiologic studies on the metabolomic profiles of GC and EC was conducted.The Newcastle–Ottawa Scale(NOS)was used to assess the quality of the included articles.Results:A total of 52 original studies were included for review.A number of metabolites were differentially distributed between GC and EC cases and non-cases,including those involved in glycolysis,anaerobic respiration,tricarboxylic acid cycle,and protein and lipid metabolism.Lactic acid,glucose,citrate,and fumaric acid were among the most frequently reported metabolites of cellular respiration while glutamine,glutamate,and valine were among the most commonly reported amino acids.The lipid metabolites identified previously included saturated and unsaturated free fatty acids,aldehydes,and ketones.However,the key findings across studies to date have been inconsistent,potentially due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group.Conclusions:Studies on metabolomics have thus far provided insights into etiological factors and biomarkers for UGI cancers,supporting the potential of applying metabolomic profiling in cancer prevention and management efforts.展开更多
BACKGROUND Study shows that signal transducer and activator of transcription 3(STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate de...BACKGROUND Study shows that signal transducer and activator of transcription 3(STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 in myeloma. STAT3 and pyruvate kinase M2(PKM2) can also be activated and enhance the Warburg effect in hepatocellular carcinoma. Precancerous lesions are critical to human and rodent hepatocarcinogenesis. However, the underlying molecular mechanism for the development of liver precancerous lesions remains unknown. We hypothesized that STAT3 promotes the Warburg effect possibly by upregulating p-PKM2 in liver precancerous lesions in rats.AIM To investigate the mechanism of the Warburg effect in liver precancerous lesions in rats.METHODS A model of liver precancerous lesions was established by a modified Solt-Farber method. The liver pathological changes were observed by HE staining and immunohistochemistry. The transformation of WB-F344 cells induced with Nmethyl-N'-nitro-N-nitrosoguanidine and hydrogen peroxide was evaluated by the soft agar assay and aneuploidy. The levels of glucose and lactate in the tissue and culture medium were detected with a spectrophotometer. The protein levels of glutathione S-transferase-π, proliferating cell nuclear antigen(PCNA), STAT3,and PKM2 were examined by Western blot and immunofluorescence.RESULTS We found that the Warburg effect was increased in liver precancerous lesions in rats. PKM2 and p-STAT3 were upregulated in activated oval cells in liverprecancerous lesions in rats. The Warburg effect, p-PKM2, and p-STAT3 expression were also increased in transformed WB-F344 cells. STAT3 activation promoted the clonal formation rate, aneuploidy, alpha-fetoprotein expression,PCNA expression, G1/S phase transition, the Warburg effect, PKM2 phosphorylation, and nuclear translocation in transformed WB-F344 cells.Moreover, the Warburg effect was inhibited by stattic, a specific inhibitor of STAT3, and further reduced in transformed WB-F344 cells after th展开更多
It has been observed that both cancer tissue cells and normal proliferating cells(NPCs)have the Warburg effect.Our goal here is to demonstrate that they do this for different reasons.To accomplish this,we have analyze...It has been observed that both cancer tissue cells and normal proliferating cells(NPCs)have the Warburg effect.Our goal here is to demonstrate that they do this for different reasons.To accomplish this,we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO.Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect,to raise the intracellular pH from 6.8 to 7.2 and to prepare for cell division energetically.Once cell cycle starts,the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release,to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral.The cells go back to the normal respirationbased ATP production once the cell division phase ends.In comparison,cancer cells have reached their intracellular pH at 7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed.Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters.Co-expression analyses suggest that lactic acid secretion is regulated by external,non-pH related signals.Overall,our data strongly suggest that the two cell types have the Warburg effect for very different reasons.展开更多
Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with o...Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.展开更多
Objective:Pyruvate kinases M(PKM),including the PKM1 and PKM2 isoforms,are critical factors in glucose metabolism.PKM2promotes aerobic glycolysis,a phenomenon known as"the Warburg effect".The purpose of this...Objective:Pyruvate kinases M(PKM),including the PKM1 and PKM2 isoforms,are critical factors in glucose metabolism.PKM2promotes aerobic glycolysis,a phenomenon known as"the Warburg effect".The purpose of this study was to identify the roles of PKM2 in regulating cellular metabolism.Methods:The CRISPR/Cas9 system was used to generate the PKM-knockout cell model to evaluate the role of PKM in cellular metabolism.Lactate levels were measured by the Vitros LAC slide method on an autoanalyzer and glucose levels were measured by the autoanalyzer AU5800.The metabolism of ^(13)C_6-glucose or ^(13)C_5-glutamine was evaluated by liquid chromatography/mass spectrometry analyses.The effects of PKM on tumor growth were detected in vivo in a tumor-bearing mouse model.Results:We found that both PKM1 and PKM2 enabled aerobic glycolysis,but PKM2 converted glucose to lactate much more efficiently than PKM1.As a result,PKM2 reduced glucose levels reserved for intracellular utilization,particularly for the production of citrate,and thus increased theα-ketoglutarate/citrate ratio to promote the generation of glutamine-derived acetylcoenzyme A through the reductive pathway.Furthermore,reductive glutamine metabolism facilitated cell proliferation under hypoxia conditions,which supports in vivo tumor growth.In addition,PKM-deletion induced a reverse Warburg effect in tumorassociated stromal cells.Conclusions:PKM2 plays a critical role in promoting reductive glutamine metabolism and maintaining proton homeostasis.This study is helpful to increase the understanding of the physiological role of PKM2 in cancer cells.展开更多
Once thought to be a waste product of oxygen limited(anaerobic)metabolism,lactate is now known to form continuously under fully oxygenated(aerobic)conditions.Lactate shuttling between producer(driver)and consumer cell...Once thought to be a waste product of oxygen limited(anaerobic)metabolism,lactate is now known to form continuously under fully oxygenated(aerobic)conditions.Lactate shuttling between producer(driver)and consumer cells fulfills at least 3 purposes;lactate is:(1)a major energy source,(2)the major gluconeogenic precursor,and(3)a signaling molecule.The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration,resuscitation from acidosis and Dengue,treatment of traumatic brain injury,maintenance of glycemia,reduction of inflammation,cardiac support in heart failure and following a myocardial infarction,and to improve cognition.Yet,dysregulated lactate shuttling disrupts metabolic flexibility,and worse,supports oncogenesis.Lactate production in cancer(the Warburg effect)is involved in all main sequela for carcinogenesis:angiogenesis,immune escape,cell migration,metastasis,and self-sufficient metabolism.The history of the tortuous path of discovery in lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B.Wolffe Lecture in Orlando,FL.展开更多
Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpresse...Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.展开更多
I want to make it very clear at the beginning of this communication;this is a controversial opinion review. However, I believe it is time to rethink our approach to cancer research and therapy. Many cancer researchers...I want to make it very clear at the beginning of this communication;this is a controversial opinion review. However, I believe it is time to rethink our approach to cancer research and therapy. Many cancer researchers, especially those involved in cancer genomic research will disagree. I welcome the disagreement and hope it will stimulate an honest debate and dialog between all disciplines of cancer research and treatment. I am convinced that a vast disconnection exists between those involved in basic research and those in the clinical arena that treat this disease. Cancer researchers in all areas should not ignore the role of cancer metabolism in tumorigenesis, progression and metastasis.展开更多
BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in ...BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated.AIM To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway.METHODS Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b.The relationship between the expression values and the clinicopathological features of the patients was investigated.Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction,while differences in protein expression were analyzed using western blot.Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2’-deoxyuridine assays,and cell cycle and apoptosis were detected using flow cytometric assays.The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay.The Warburg effect was evaluated by glucose uptake and lactic acid production assays.RESULTS The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls(P<0.05).Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC,including stage I,II-III,and IV.Furthermore,the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification.HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway,thereby promoting proliferation of HCT116 and SW620 cells.However,the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b,effectively blocking the Warburg effect.CONCLUSION These findings suggest that the novel miR-49展开更多
Cancer reprogramming is an important facilitator of cancer development and survival,with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation,even under sufficient oxygen supply ...Cancer reprogramming is an important facilitator of cancer development and survival,with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation,even under sufficient oxygen supply condition.This metabolic alteration,known as the Warburg effect,serves as a significant indicator of malignant tumor transformation.The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells.Key enzymes involved in this process include glucose transporters(GLUTs),HKs,PFKs,LDHs,and PKM2.Moreover,the expression of transcriptional regulatory factors and proteins,such as FOXM1,p53,NF-κB,HIF1a,and c-Myc,can also influence cancer progression.Furthermore,lncRNAs,miRNAs,and circular RNAs play a vital role in directly regulating the Warburg effect.Additionally,gene mutations,tumor microenvironment remodeling,and immune system interactions are closely associated with the Warburg effect.Notably,the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment.This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.展开更多
Objective:To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme(GBM).Methods:GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47(TRIM47)in GBM patients...Objective:To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme(GBM).Methods:GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47(TRIM47)in GBM patients.RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells.LN-229 cell proliferation,migration as well as invasion were estimated by CCK-8,colony formation,wound healing,and Transwell assays following interference with NUDT5.ECAR assay,L-lactic acid kit,glucose detection kit,and ATP detection kit were applied for the detection of glycolysis-related indexes.Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47.Results:GEPIA database showed that NUDT5 expression was significantly increased in GBM patients.Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability,proliferation,invasion,migration,and glycolysis of GBM cells.Moreover,TRIM47 was highly expressed in GBM cells and interacted with NUDT5.Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation,metastasis,and glycolysis of GBM cells.Conclusions:NUDT5 promotes the growth,metastasis,and Warburg effect of GBM cells by upregulating TRIM47.Both NUDT5 and TRIM47 can be used as targets for GMB treatment.展开更多
Cancer cells reprogram their gene expression to promote growth,survival,proliferation,and invasiveness.The unique expression of certain uptake transporters in cancers and their innate function to concentrate small mol...Cancer cells reprogram their gene expression to promote growth,survival,proliferation,and invasiveness.The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells.In this review,we focus on several solute carrier(SLC)transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells,including the sodium/iodine symporter(NIS),norepinephrine transporter(NET),glucose transporter 1(GLUT1),and monocarboxylate transporters(MCTs).The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents[e.g.,Ⅰ-123,Ⅰ-131,123Ⅰ-iobenguane(mIBG),18F-fluorodeoxyglucose(18F-FDG)and 13C pyruvate].Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed.Finally,we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment.By analyzing the few clinically successful examples,we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.展开更多
Metastasis-associated in colon cancer-1(MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in ca...Metastasis-associated in colon cancer-1(MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer(GC), MACC1 has been shown to be involved in oncogenesis and t umor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelialto-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry(VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment.展开更多
基金Supported by The China Scholarship CouncilNo.[2014]3012
文摘Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells. Upregulated aerobic glycolysis(Warburg effect) in gastric cancer meeting the demands of cell proliferation is associated with genetic mutations, epigenetic modification and proteomic alteration. Understanding the mechanisms of aerobic glycolysis may contribute to our knowledge of gastric carcinogenesis. Metabolomic studies offer novel, convenient and practical tools in the search for new biomarkers for early detection, diagnosis, prognosis, and chemosensitivity prediction of gastric cancer. Interfering with the process of glycolysis in cancer cells may provide a new and promising therapeutic strategy for gastric cancer. In this article, we present a brief review of recent studies of glucose metabolism in gastric cancer, with primary focus on the clinical applications of new biomarkers and their potential therapeutic role in gastric cancer.
文摘Hepatocellular carcinoma(HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg's phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.
文摘Pyruvate kinase isoform M2 （PKM2） converts phospho- enolpyruvate （PEP） to pyruvate and plays an important role in cancer metabolism. Here, we show that post- translational modifications and a patient-derived muta- tion regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a ＂seesaw＂ model to illustrate confor- mational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2^Y105E （phos- phorylation mimic of Y105） decreases pyruvate kinase activity by inhibiting FBP （fructose 1,6-bisphosphate）- induced R-state formation, and PKM2K^3305Q （acetylation mimic of K305） abolishes the activity by hindering tet- ramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post- translational modifications and a patient-derived muta- tion and provides a structural basis for further investi- gation of other modifications and mutations of PKM2 yet to be discovered.
基金supported by grants from the American Cancer Society(RSG-10-160-01-LIB,to GP)Melanoma Research Alliance(to GP)and the NIH(AI097852,AI094478 and CA184379 to GP).
文摘Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival,proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment.A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer treatments.Toll-like receptors(TLRs)have recently been recognized as critical factors involved in tumor pathogenesis,regulating both tumor cells and tumor-infiltrating innate and adaptive immune cells.However,little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism,although there is abundant expression of TLRs in these cells.In this review,we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor microenvironment.In particular,we discuss how malignant tumors regulate metabolism to support their growth and survival,summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells,and further explore potential strategies targeting cell metabolism for TLR-based cancer therapy.An improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.
基金supported by grants from the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research(Grant No.BMU2020JI004)Capital’s Funds for Health Improvement and Research(CFH)。
文摘Objective:Upper gastrointestinal(UGI)cancers,predominantly gastric cancer(GC)and esophageal cancer(EC),are malignant tumor types with high morbidity and mortality rates.Accumulating studies have focused on metabolomic profiling of UGI cancers in recent years.In this systematic review,we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with GC and EC.Methods:A systematic search of three databases(Embase,PubMed,and Web of Science)for molecular epidemiologic studies on the metabolomic profiles of GC and EC was conducted.The Newcastle–Ottawa Scale(NOS)was used to assess the quality of the included articles.Results:A total of 52 original studies were included for review.A number of metabolites were differentially distributed between GC and EC cases and non-cases,including those involved in glycolysis,anaerobic respiration,tricarboxylic acid cycle,and protein and lipid metabolism.Lactic acid,glucose,citrate,and fumaric acid were among the most frequently reported metabolites of cellular respiration while glutamine,glutamate,and valine were among the most commonly reported amino acids.The lipid metabolites identified previously included saturated and unsaturated free fatty acids,aldehydes,and ketones.However,the key findings across studies to date have been inconsistent,potentially due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group.Conclusions:Studies on metabolomics have thus far provided insights into etiological factors and biomarkers for UGI cancers,supporting the potential of applying metabolomic profiling in cancer prevention and management efforts.
基金Supported by the National Natural Science Foundation of China,No.81070319the Beijing Natural Science Foundation of China,No.7102013the Beijing Municipal Education Commission Research Program,China,No.KM201610025004
文摘BACKGROUND Study shows that signal transducer and activator of transcription 3(STAT3) can increase the Warburg effect by stimulating hexokinase 2 in breast cancer and upregulate lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 in myeloma. STAT3 and pyruvate kinase M2(PKM2) can also be activated and enhance the Warburg effect in hepatocellular carcinoma. Precancerous lesions are critical to human and rodent hepatocarcinogenesis. However, the underlying molecular mechanism for the development of liver precancerous lesions remains unknown. We hypothesized that STAT3 promotes the Warburg effect possibly by upregulating p-PKM2 in liver precancerous lesions in rats.AIM To investigate the mechanism of the Warburg effect in liver precancerous lesions in rats.METHODS A model of liver precancerous lesions was established by a modified Solt-Farber method. The liver pathological changes were observed by HE staining and immunohistochemistry. The transformation of WB-F344 cells induced with Nmethyl-N'-nitro-N-nitrosoguanidine and hydrogen peroxide was evaluated by the soft agar assay and aneuploidy. The levels of glucose and lactate in the tissue and culture medium were detected with a spectrophotometer. The protein levels of glutathione S-transferase-π, proliferating cell nuclear antigen(PCNA), STAT3,and PKM2 were examined by Western blot and immunofluorescence.RESULTS We found that the Warburg effect was increased in liver precancerous lesions in rats. PKM2 and p-STAT3 were upregulated in activated oval cells in liverprecancerous lesions in rats. The Warburg effect, p-PKM2, and p-STAT3 expression were also increased in transformed WB-F344 cells. STAT3 activation promoted the clonal formation rate, aneuploidy, alpha-fetoprotein expression,PCNA expression, G1/S phase transition, the Warburg effect, PKM2 phosphorylation, and nuclear translocation in transformed WB-F344 cells.Moreover, the Warburg effect was inhibited by stattic, a specific inhibitor of STAT3, and further reduced in transformed WB-F344 cells after th
基金funding support from Georgia Research Alliance,the National Natural Science Foundation of China(Grant Nos.61472158,61572228,and 61572227)the Premier-Discipline Enhancement Scheme supported by Zhuhai Government and Premier Key-Discipline Enhancement Scheme supported by Guangdong Government,China
文摘It has been observed that both cancer tissue cells and normal proliferating cells(NPCs)have the Warburg effect.Our goal here is to demonstrate that they do this for different reasons.To accomplish this,we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO.Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect,to raise the intracellular pH from 6.8 to 7.2 and to prepare for cell division energetically.Once cell cycle starts,the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release,to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral.The cells go back to the normal respirationbased ATP production once the cell division phase ends.In comparison,cancer cells have reached their intracellular pH at 7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed.Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters.Co-expression analyses suggest that lactic acid secretion is regulated by external,non-pH related signals.Overall,our data strongly suggest that the two cell types have the Warburg effect for very different reasons.
基金supported by grants from the Key Program of Zhejiang Provincial Natural Science Foundation(Grant No.LZ17H160002)National Natural Science Foundation of China(Grant No.81972456 and 81772801)+2 种基金the National Key R&D Program of China(Grant No.2016YFC1303200)the Fundamental Research Funds for Central Universities of China(to C.D.)the Thousand Young Talents Plan of China(to C.D.)。
文摘Since triple-negative breast cancer(TNBC)was first defined over a decade ago,increasing studies have focused on its genetic and molecular characteristics.Patients diagnosed with TNBC,compared to those diagnosed with other breast cancer subtypes,have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment.Metabolic reprogramming,an emerging hallmark of cancer,is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands;maintain the redox balance;and further promote oncogenic signaling,cell proliferation,and metastasis.Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC.Here,we review the metabolic reprogramming of glycolysis,oxidative phosphorylation,amino acid metabolism,lipid metabolism,and other branched pathways in TNBC and explore opportunities for new biomarkers,imaging modalities,and metabolically targeted therapies.
基金supported by the funds from National Natural Science Foundation of China(Grant No.81672762,81622037 and 81602446)
文摘Objective:Pyruvate kinases M(PKM),including the PKM1 and PKM2 isoforms,are critical factors in glucose metabolism.PKM2promotes aerobic glycolysis,a phenomenon known as"the Warburg effect".The purpose of this study was to identify the roles of PKM2 in regulating cellular metabolism.Methods:The CRISPR/Cas9 system was used to generate the PKM-knockout cell model to evaluate the role of PKM in cellular metabolism.Lactate levels were measured by the Vitros LAC slide method on an autoanalyzer and glucose levels were measured by the autoanalyzer AU5800.The metabolism of ^(13)C_6-glucose or ^(13)C_5-glutamine was evaluated by liquid chromatography/mass spectrometry analyses.The effects of PKM on tumor growth were detected in vivo in a tumor-bearing mouse model.Results:We found that both PKM1 and PKM2 enabled aerobic glycolysis,but PKM2 converted glucose to lactate much more efficiently than PKM1.As a result,PKM2 reduced glucose levels reserved for intracellular utilization,particularly for the production of citrate,and thus increased theα-ketoglutarate/citrate ratio to promote the generation of glutamine-derived acetylcoenzyme A through the reductive pathway.Furthermore,reductive glutamine metabolism facilitated cell proliferation under hypoxia conditions,which supports in vivo tumor growth.In addition,PKM-deletion induced a reverse Warburg effect in tumorassociated stromal cells.Conclusions:PKM2 plays a critical role in promoting reductive glutamine metabolism and maintaining proton homeostasis.This study is helpful to increase the understanding of the physiological role of PKM2 in cancer cells.
文摘Once thought to be a waste product of oxygen limited(anaerobic)metabolism,lactate is now known to form continuously under fully oxygenated(aerobic)conditions.Lactate shuttling between producer(driver)and consumer cells fulfills at least 3 purposes;lactate is:(1)a major energy source,(2)the major gluconeogenic precursor,and(3)a signaling molecule.The Lactate Shuttle theory is applicable to diverse fields such as sports nutrition and hydration,resuscitation from acidosis and Dengue,treatment of traumatic brain injury,maintenance of glycemia,reduction of inflammation,cardiac support in heart failure and following a myocardial infarction,and to improve cognition.Yet,dysregulated lactate shuttling disrupts metabolic flexibility,and worse,supports oncogenesis.Lactate production in cancer(the Warburg effect)is involved in all main sequela for carcinogenesis:angiogenesis,immune escape,cell migration,metastasis,and self-sufficient metabolism.The history of the tortuous path of discovery in lactate metabolism and shuttling was discussed in the 2019 American College of Sports Medicine Joseph B.Wolffe Lecture in Orlando,FL.
文摘Objective: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II(HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells.Methods: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase(PDHA1) was tested in HEK293 T cells and clear cell renal cell carcinoma(cc RCC) specimens using gene knockdown, western blotting,immunohistochemistry, and immunofluorescence.Results: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase(PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in cc RCC.Conclusions: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.
文摘I want to make it very clear at the beginning of this communication;this is a controversial opinion review. However, I believe it is time to rethink our approach to cancer research and therapy. Many cancer researchers, especially those involved in cancer genomic research will disagree. I welcome the disagreement and hope it will stimulate an honest debate and dialog between all disciplines of cancer research and treatment. I am convinced that a vast disconnection exists between those involved in basic research and those in the clinical arena that treat this disease. Cancer researchers in all areas should not ignore the role of cancer metabolism in tumorigenesis, progression and metastasis.
基金Supported by the National Natural Science Foundation of China,No.82160405Jiangxi Provincial Natural Science Foundation,No.20232BAB206131,No.20212ACB206016,and No.20224BAB206114+1 种基金Jiangxi Provincial Health Commission Project,No.202310887the Development Fund of Jiangxi Cancer Hospital,No.2021J10.
文摘BACKGROUND Heterogeneous ribonucleoprotein A1(hnRNPA1)has been reported to enhance the Warburg effect and promote colon cancer(CC)cell proliferation,but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated.AIM To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway.METHODS Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b.The relationship between the expression values and the clinicopathological features of the patients was investigated.Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction,while differences in protein expression were analyzed using western blot.Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2’-deoxyuridine assays,and cell cycle and apoptosis were detected using flow cytometric assays.The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay.The Warburg effect was evaluated by glucose uptake and lactic acid production assays.RESULTS The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls(P<0.05).Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC,including stage I,II-III,and IV.Furthermore,the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification.HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway,thereby promoting proliferation of HCT116 and SW620 cells.However,the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b,effectively blocking the Warburg effect.CONCLUSION These findings suggest that the novel miR-49
基金supported in part by National Natural Science Foundation of China(Grant No.82172649,82003580,and 82173666)Shenzhen science and technology research and development funds(Grant No.JCYJ20210324094612035,China)。
文摘Cancer reprogramming is an important facilitator of cancer development and survival,with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation,even under sufficient oxygen supply condition.This metabolic alteration,known as the Warburg effect,serves as a significant indicator of malignant tumor transformation.The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells.Key enzymes involved in this process include glucose transporters(GLUTs),HKs,PFKs,LDHs,and PKM2.Moreover,the expression of transcriptional regulatory factors and proteins,such as FOXM1,p53,NF-κB,HIF1a,and c-Myc,can also influence cancer progression.Furthermore,lncRNAs,miRNAs,and circular RNAs play a vital role in directly regulating the Warburg effect.Additionally,gene mutations,tumor microenvironment remodeling,and immune system interactions are closely associated with the Warburg effect.Notably,the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment.This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.
文摘Objective:To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme(GBM).Methods:GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47(TRIM47)in GBM patients.RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells.LN-229 cell proliferation,migration as well as invasion were estimated by CCK-8,colony formation,wound healing,and Transwell assays following interference with NUDT5.ECAR assay,L-lactic acid kit,glucose detection kit,and ATP detection kit were applied for the detection of glycolysis-related indexes.Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47.Results:GEPIA database showed that NUDT5 expression was significantly increased in GBM patients.Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability,proliferation,invasion,migration,and glycolysis of GBM cells.Moreover,TRIM47 was highly expressed in GBM cells and interacted with NUDT5.Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation,metastasis,and glycolysis of GBM cells.Conclusions:NUDT5 promotes the growth,metastasis,and Warburg effect of GBM cells by upregulating TRIM47.Both NUDT5 and TRIM47 can be used as targets for GMB treatment.
基金supported by the National Institutes of Health(NIH)National Institute of General Medical Sciences(Grant R01 GM066233,USA).
文摘Cancer cells reprogram their gene expression to promote growth,survival,proliferation,and invasiveness.The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells.In this review,we focus on several solute carrier(SLC)transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells,including the sodium/iodine symporter(NIS),norepinephrine transporter(NET),glucose transporter 1(GLUT1),and monocarboxylate transporters(MCTs).The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents[e.g.,Ⅰ-123,Ⅰ-131,123Ⅰ-iobenguane(mIBG),18F-fluorodeoxyglucose(18F-FDG)and 13C pyruvate].Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed.Finally,we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment.By analyzing the few clinically successful examples,we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.
文摘Metastasis-associated in colon cancer-1(MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer(GC), MACC1 has been shown to be involved in oncogenesis and t umor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelialto-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry(VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment.
