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Cell Oct 2019We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues...
We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated proteogenomic analyses revealed consistency and discordance among multi-omics, activation status of key signaling pathways, and liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical and molecular attributes including patient survival, tumor thrombus, genetic profile, and the liver-specific proteome. These proteomic subgroups have distinct features in metabolic reprogramming, microenvironment dysregulation, cell proliferation, and potential therapeutics. Two prognostic biomarkers, PYCR2 and ADH1A, related to proteomic subgrouping and involved in HCC metabolic reprogramming, were identified. CTNNB1 and TP53 mutation-associated signaling and metabolic profiles were revealed, among which mutated CTNNB1-associated ALDOA phosphorylation was validated to promote glycolysis and cell proliferation. Our study provides a valuable resource that significantly expands the knowledge of HBV-related HCC and may eventually benefit clinical practice.
Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Cohort Studies; Female; Fructose-Bisphosphate Aldolase; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Middle Aged; Proteogenomics; Tumor Microenvironment; beta Catenin
PubMed: 31585088
DOI: 10.1016/j.cell.2019.08.052 -
Nature Metabolism Oct 2022The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are...
The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.
Topics: Humans; Male; Mice; Animals; AMP-Activated Protein Kinases; Glucose; Fructose-Bisphosphate Aldolase; Lysosomes; Starvation; Adenosine Triphosphatases; Caenorhabditis elegans; Adenosine Monophosphate; Fructose; Insulins
PubMed: 36217034
DOI: 10.1038/s42255-022-00640-7 -
Advanced Science (Weinheim,... Jun 2021Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor...
Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single-cell RNA sequencing. HCC272 with high status of epithelia-mesenchymal transition proves broad-spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo-time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta-1 (CTNNB1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak-STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N-Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance.
Topics: Antigens, Neoplasm; Carbonic Anhydrase IX; Cell Cycle Proteins; Digestive System Diseases; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fructose-Bisphosphate Aldolase; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Hyaluronan Receptors; Intracellular Signaling Peptides and Proteins; Janus Kinases; Neoplastic Stem Cells; Organoids; RNA, Long Noncoding; RNA-Seq; STAT Transcription Factors; Single-Cell Analysis; Transcriptome; beta Catenin
PubMed: 34105295
DOI: 10.1002/advs.202003897 -
Cell Reports. Medicine Sep 2023Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain...
Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.
Topics: Humans; Carcinoma, Pancreatic Ductal; Fructose-Bisphosphate Aldolase; Glucose; Glucose Transporter Type 1; Glucosephosphate Dehydrogenase; Pancreatic Neoplasms
PubMed: 37597521
DOI: 10.1016/j.xcrm.2023.101162 -
Nature Metabolism Sep 2020The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1...
The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMP-activated protein kinase to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the GAPDH-catalysed steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from DHA is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.
Topics: AMP-Activated Protein Kinases; Dihydroxyacetone; Dihydroxyacetone Phosphate; Energy Metabolism; Fructose-Bisphosphate Aldolase; Glucose; Glycolysis; HEK293 Cells; Humans; Lipid Metabolism; Phosphotransferases (Alcohol Group Acceptor); TOR Serine-Threonine Kinases
PubMed: 32719541
DOI: 10.1038/s42255-020-0250-5 -
Basic Research in Cardiology Nov 2023Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological... (Review)
Review
Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia-reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.
Topics: Humans; Cardiovascular Diseases; Heart Failure; Oxidative Phosphorylation; Aldehyde-Lyases; Metabolic Networks and Pathways
PubMed: 37938421
DOI: 10.1007/s00395-023-01018-w -
Nature Communications Mar 2020Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment....
Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.
Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Large-Core Needle; Breast; Cell Line, Tumor; Chemotherapy, Adjuvant; Cisplatin; DNA Damage; Datasets as Topic; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Fructose-Bisphosphate Aldolase; Gene Knockdown Techniques; Glycolysis; Humans; MAP Kinase Signaling System; Mastectomy; Mice; Middle Aged; Neoadjuvant Therapy; Nucleotides; Pentose Phosphate Pathway; RNA, Small Interfering; Treatment Outcome; Triple Negative Breast Neoplasms; Up-Regulation; Xenograft Model Antitumor Assays; rac1 GTP-Binding Protein
PubMed: 32193458
DOI: 10.1038/s41467-020-15308-7 -
Hepatology (Baltimore, Md.) Sep 2021Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell...
BACKGROUND AND AIMS
Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC.
APPROACH AND RESULTS
From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC.
CONCLUSIONS
Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.
Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Fructose-Bisphosphate Aldolase; Gene Knockdown Techniques; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Liver Neoplasms; Loss of Function Mutation; Mice; Neoplasm Transplantation; Sulfamonomethoxine; Tumor Hypoxia; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 33813748
DOI: 10.1002/hep.31846 -
Cell Metabolism Sep 2019Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits...
Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.
Topics: AMP-Activated Protein Kinases; Acrylamides; Adenosine Triphosphatases; Animals; Bridged Bicyclo Compounds, Heterocyclic; Caenorhabditis elegans; Calcium; Calcium Channels; Endoplasmic Reticulum; Enzyme Activation; Fructose-Bisphosphate Aldolase; Gene Knockout Techniques; Glucose; HEK293 Cells; Humans; Lysosomes; Male; Mice; Signal Transduction; TRPV Cation Channels; Transfection
PubMed: 31204282
DOI: 10.1016/j.cmet.2019.05.018 -
Applied Microbiology and Biotechnology Nov 2021Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the... (Review)
Review
Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research.Key points• Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science.• Enzyme catalysis is essential for the synthesis of fluorinated compounds.• The loop structure of fluorinase is the key to forming the C-F bond.
Topics: Aldehyde-Lyases; Catalysis; Fluorine; Halogenation; Transaminases
PubMed: 34625820
DOI: 10.1007/s00253-021-11608-0