• UK Biobank
• cancer
• exome sequencing
• family history
• power calculations
• protein‐truncating variants

• Humans
• United Kingdom/epidemiology
• Neoplasms/genetics
• Neoplasms/epidemiology
• Biological Specimen Banks
• Genetic Predisposition to Disease
• Monte Carlo Method
• Exome Sequencing
• Genetic Variation
• UK Biobank

• N.W. was supported by the International Alliance for Cancer Early Detection, an alliance between Cancer Research UK (C14478/A29329), Canary Center at Stanford University, the University of Cambridge, OHSU Knight Cancer Institute, University College London and the University of Manchester. J.D. was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312). X.W. and J.P.T. were supported by Cancer Research UK (PPRPGM-Nov20\100002, PRCPJT-May21\100006 and G110748).
• QC of the data has been funded by the Medical Research Council (unit programmes: MC_UU_12015/2, MC_UU_00006/2).

• Chemotherapy resistance
• aldolase
• enolase
• glyceraldehyde 3-phosphate dehydrogenase
• hexokinase
• lactate dehydrogenase.
• phosphofructokinase
• phosphoglycerate kinase
• pyruvate kinase

• Humans
• Drug Resistance, Neoplasm/genetics
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/genetics
• Neoplasms/pathology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Glycolysis/drug effects
• Animals
• Gene Expression Regulation, Neoplastic/drug effects

• Humans
• Risk Factors
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/prevention & control
• Inflammatory Bowel Diseases/diagnosis
• Biomarkers

• NSERC

• Hic-5
• ZNF395
• metastasis
• reactive oxygen species modulator
• stable nucleic acids lipid nanoparticles

• Humans
• Vascular Endothelial Growth Factor A
• Computational Biology
• Ataxia Telangiectasia
• Cell Movement
• Colorectal Neoplasms/genetics

• Crotonylation
• Embryonic stem cell
• Endodermal differentiation
• GAPDH
• Metabolic switch

• 2017A030313093 Natural Science Foundation of Guangdong Province
• 2019A1515011422 Basic and Applied Basic Research Foundation of Guangdong Province

• HuCCT1
• Src nonreceptor tyrosine kinase
• TFK1
• cholangiocarcinoma
• glyceraldehyde-3-phosphate dehydrogenase
• hydrogen peroxide clone-5

• LUAD
• drug response
• immune infiltration
• nomogram
• oxidative stress

• National Natural Science Foundation of China

Bone cancer pain is a common symptom in cancer patients with bone metastases and its underlying mechanisms remain unknown. Here, we report that Runx1 directly upregulates the transcriptional activity of P2X3 receptor (P2X3R) gene promoter in PC12 cells. Knocking down Runx1 in dorsal root ganglion (DRG) neurons suppresses the functional upregulation of P2X3R, attenuates neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas overexpressing Runx1 promotes P2X3R gene transcription in DRG neurons, induces neuronal hyperexcitability and pain hypersensitivity in naïve rats. Activation of GDNF-GFRα1-Ret-ERK signaling is required for Runx1-mediated P2X3R gene transcription in DRG neurons, and contributes to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. These findings indicate that the Runx1-mediated P2X3R gene transcription resulted from activation of GDNF-GFRα1-Ret-ERK signaling contributes to the sensitization of DRG neurons and pathogenesis of bone cancer pain. Our findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.

•

Runx1 directly upregulates the transcriptional activity of P2X3R gene promoter

• 3-Bromopyruvate
• Breast cancer
• Cancer metabolism
• Cytoskeleton

Colorectal cancer (CRC) is the most diagnosed cancer with the highest mortality rate each year globally. Although there are treatments for CRC, the development of resistance to therapies decreases the success of treatments. In vitro studies using the Caco-2 cell line have revealed the anticancer properties of silver nanoparticles (AgNPs) as a possible treatment for this disease. This study considered four researches that evaluated the proteomic profiles of cells of the Caco-2 line exposed to AgNPs. We performed a bioinformatics analysis to predict protein-protein interaction, hub genes, Gene Ontology (molecular function, biological process, and cellular components), KEGG pathways, analysis of expression, and immune cell infiltration. For these analyses, the STRING, DAVID, UALCAN, GEPIA2, and TISIDB databases were used. The results in Gene Ontology show that AgNPs cause a deregulation of genes related to cell-cell adhesion, the cytoplasm, the centriole, and carbon metabolism. Hub genes were identified, including GADPH, ENO1, EEF2, and ATP5A1, which showed differential expression in patients with adenocarcinoma of the colon and rectum. Additionally, the expression of the hub genes and immune cells was correlated. It was found that ATP5A1 and ENO1 were positively correlated with the infiltration of CD4+ T lymphocytes in colon adenocarcinoma and a negative correlation between GADPH and PDIA3 with the infiltration of NK cells and CD4+ T lymphocytes in rectal adenocarcinoma, respectively. In conclusion, the administration of AgNPs causes an alteration of biological processes, cellular components, metabolic pathways, deregulation of hub genes, and the activity of immune cells leading to a potential anticancer effect.

Immune checkpoint inhibitor-mediated immunotherapy cannot be carried out on a large scale clinically due to its low universality. In recent years, cyclic guanosine monophosphate synthase/interferon gene stimulating factor (cGAS/STING)-mediated innate immune signaling pathway-mediated immunotherapy has attracted more and more attention. In addition, metabolic inhibitors also show good effects on tumor treatment, but their application is often limited because of their large first pass effect or difficult administration.

The particle size and potential parameters were measured by DLS. In order to determine the optimal ratio of the two drugs, we calculated the CI value of different nanoparticles through MTT experiment, and simulated their synergistic effect through Gaussian software. Then the morphology and crystal form of the best proportion of drugs were studied by TEM and XRD. The anti-tumor mechanism of composite nanoparticles was confirmed by the determination of metabolic related indexes, Q-PCR and WB. The antitumor effect and immune activation effect were comprehensively evaluated by in vivo and in vitro experiments.

Here, we found and synthesized BCP nanoparticles ((BPA + CPI) @ PLGA NPs) which can effectively reduce the metabolism of tumor cells and inhibit cell proliferation. At the same time, the release of mitochondrial DNA (mtDNA) caused by mitochondrial metabolism disorder further activated the cGAS/STING signal pathway in Hepa1–6 cells. We found that the drug-treated Hepa1–6 cells had obvious TBK1 phosphorylation and STING dimerization. Combined with STING agonist, it could effectively promote the activation of CD8 T cells and enhanced the therapeutic effect on liver cancer.

Our results showed that PLGA nanocarrier can successfully improve the dosage forms of two metabolic inhibitors and show the effect of synergistic therapy. BCP nanoparticles can also activate the innate immunity of tumor cells and significantly enhance tumor inhibition after combined with STING agonists. This study has high reference and transformation value for the combined treatment of immunosuppression and metabolic inhibition.

The online version contains supplementary material available at 10.1186/s12951-022-01241-y.

• Hepa1–6 cells
• Metabolism inhibitors
• STING agonists
• cGAS/STING

• Cancer
• RPS13
• Reference genes
• TCGA
• q-PCR

• Databases, Genetic
• Gene Expression/genetics
• Gene Expression Profiling/methods
• Gene Expression Profiling/standards
• Humans
• Neoplasms/diagnosis
• Neoplasms/genetics
• Real-Time Polymerase Chain Reaction/methods
• Reference Standards
• Ribosomal Proteins/genetics
• Ribosomal Proteins/metabolism
• Transcriptome/genetics

• Attribute clustering
• DNA Microarray
• Ensemble classifier
• Filter
• Gene expression data
• Machine learning

• Carcinogenesis
• Carcinoma
• Database
• Network biology
• System biology
• Targets

• Animals
• Antigens, CD
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Aquatic Organisms/chemistry
• Aspergillus/chemistry
• Benzophenones/pharmacology
• Cadherins
• Colorectal Neoplasms/drug therapy
• G2 Phase Cell Cycle Checkpoints/drug effects
• Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists & inhibitors
• HCT116 Cells
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Xenograft Model Antitumor Assays
• Mice

• NAD biology
• NAD dehydrogenases
• cancer
• drug discovery and design
• malaria
• tuberculosis

• Antiproliferative activity
• Covalent inhibitors
• Cysteine modification
• Electrophilic warhead
• GAPDH

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antiparasitic Agents/chemistry
• Antiparasitic Agents/pharmacology
• Drug Design
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists & inhibitors
• Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry
• Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism
• Humans

• apoptosis
• cancer
• cell cycle
• evolution
• moonlighting
• pathogenesis

• Cancer
• Glyceraldehyde-3-phosphate dehydrogenase
• Glycolysis
• Inhibitor
• Virtual screening

A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells.

• HIF
• STAT3
• STAT5
• Warburg effect
• cancer metabolism
• transcription factors

• 3-BrPA
• Dendritic cells
• Glioma microenvironment
• MCT1
• Macrophages

• 3-BP
• TRAIL
• TRAIL resistance
• apoptose
• apoptosis
• cancer colorectal
• colorectal cancer
• résistance à TRAIL

Several studies indicate that the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has pleiotropic functions independent of its canonical role in glycolysis. The GAPDH functional diversity is mainly due to post-translational modifications in different amino acid residues or due to protein–protein interactions altering its localization from cytosol to nucleus, mitochondria or extracellular microenvironment. Non-glycolytic functions of GAPDH include the regulation of cell death, autophagy, DNA repair and RNA export, and they are observed in physiological and pathological conditions as cancer and neurodegenerative disorders. In disease, the knowledge of the mechanisms regarding GAPDH-mediated cell death is becoming fundamental for the identification of novel therapies. Here, we elucidate the correlation between autophagy and GAPDH in cancer, describing the molecular mechanisms involved and its impact in cancer development. Since autophagy is a degradative pathway associated with the regulation of cell death, we discuss recent evidence supporting GAPDH as a therapeutic target for autophagy regulation in cancer therapy. Furthermore, we summarize the molecular mechanisms and the cellular effects of GAPDH aggregates, which are correlated with mitochondrial malfunctions and can be considered a potential therapeutic target for various diseases, including cancer and neurodegenerative disorders.

• GAPDH
• aggregates
• autophagy
• cancer
• cell death

• Animals
• Autophagy/physiology
• Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism
• Humans
• Models, Biological
• Neoplasms/metabolism
• Neurodegenerative Diseases/metabolism

Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

• 3-bromopyruvate
• aerobic glycolysis
• antitumor effect
• glycolytic inhibitor
• tumor energy metabolism

Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and characterized by development of tumors in multiple organs including the kidneys. TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, leading to aberrant activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to glucose and glutamine in Tsc1^−/−or Tsc2^−/− mouse embryonic fibroblasts (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic inhibition causes significant cell death in Tsc2^−/− but not Tsc2^+/+ MEFs. In this study, we tested efficacy of dual inhibition of glycolysis with 3-BrPA and glutaminolysis with CB-839 for renal tumors in Tsc2^+/− mice. Following 2 months of treatment of Tsc2^+/− mice from the age of 12 months, combination of 3-BrPA and CB-839 significantly reduced overall size and cellular areas of all renal lesions (cystic/papillary adenomas and solid carcinomas), but neither alone did. Combination of 3-BrPA and CB-839 inhibited mTORC1 and the proliferation of tumor cells but did not increase apoptosis. However, combination of 3-BrPA and CB-839 was not as efficacious as rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 for renal lesions of Tsc2^+/− mice. Consistently, rapamycin alone or rapamycin in combination with either 3-BrPA or CB-839 had stronger inhibitory effects on mTORC1 and proliferation of tumor cells than combination of 3-BrPA and CB-839. We conclude that combination of 3-BRPA and CB-839 may not offer a better therapeutic strategy than rapamycin for TSC-associated tumors.

In rapid proliferating cancer cells, there is a need for fast ATP and lactate production, therefore cancer cells turn off oxidative phosphorylation and turn on the so called "Warburg effect". This regulating the expression of genes involved in glycolysis. According to many studies, glucose transporter 1, which supplies glucose to the cell, is the most abundantly expressed transporter in cancer cells. Hexokinase 2, is one of four hexokinase isoenzymes, is also another highly expressed enzyme in cancer cells and it functions to enhance the glycolytic rate. The up-regulation of these two proteins has been established as an important factor in promoting development and metastasis in many types of cancer. Furthermore, other enzymes involved in glycolysis pathway such as phosphoglucose isomerase and glyceraldehyde 3-phosphate dehydrogenase, exhibit additional functions in promoting tumor growth in a non-glycolytic way. This review demonstrates the pivotal role of GLUT1, HK2, PGI and GAPDH in cancer development. In particular, we look at how the multifunctional proteins, PGI and GAPDH, affect cancer cell survival. We also present various clinical cancer cases in terms of the overexpression of selected proteins, which may be considered as a therapeutic target.

• Glucose transporter 1
• cancer development
• glyceraldehyde 3-phosphate dehydrogenase
• hexokinase 2
• phosphoglucose isomerase

• Derris scandens
• apoptosis
• hepatocellular carcinoma
• hepatocellular carcinoma cell line HCC-S102
• proteomics

• cancer cell metabolism
• cardiac metabolism
• clinical trials as topic
• heart failure
• intermediary metabolism
• metabolic targets
• systems biology
• targeted treatments

• Colon cancer
• High grade dysplasia
• Interactome
• Transcriptome

• Bromopyruvate
• Monocarboxylate transporter
• Perillyl alcohol
• Protein alkylation

• Animals
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Colonic Neoplasms/genetics
• Colonic Neoplasms/pathology
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists & inhibitors
• Glyceraldehyde-3-Phosphate Dehydrogenases/genetics
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/secondary
• Mice
• Neoplasm Metastasis
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• RNA, Small Interfering/genetics
• Snail Family Transcription Factors/biosynthesis
• Snail Family Transcription Factors/genetics
• Sp1 Transcription Factor/biosynthesis
• Sp1 Transcription Factor/genetics
• Xenograft Model Antitumor Assays

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.

• PEL/non-Hodgkin lymphoma
• PI3K/Akt/mTOR inhibitors
• Warburg phenotype
• glycolyis inhibitors
• hypoxia

• Biomarker
• DLBCL
• Heat shock protein
• MALDI IMS
• Proteome

• Biomarkers
• Diagnosis, Differential
• HIV Infections/complications
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lymph Nodes/metabolism
• Lymph Nodes/pathology
• Lymphoma, Large B-Cell, Diffuse/complications
• Lymphoma, Large B-Cell, Diffuse/diagnosis
• Lymphoma, Large B-Cell, Diffuse/metabolism
• Lymphoma, Large B-Cell, Diffuse/mortality
• Peptides/metabolism
• Prognosis
• Proteome
• Proteomics/methods
• Pseudolymphoma/complications
• Pseudolymphoma/diagnosis
• Pseudolymphoma/metabolism
• Signal Transduction

Glycolysis provides precursors for the synthesis of macromolecules and may contribute to the ATP supply required for the constant and accelerated cellular duplication in cancer cells. In consequence, inhibition of glycolysis has been reiteratively considered as an anti-cancer therapeutic option. In previous studies, kinetic modeling of glycolysis in cancer cells allowed the identification of the main steps that control the glycolytic flux: glucose transporter, hexokinase (HK), hexose phosphate isomerase (HPI), and glycogen degradation in human cervix HeLa cancer cells and rat AS-30D ascites hepatocarcinoma. It was also previously experimentally determined that simultaneous inhibition of the non-controlling enzymes lactate dehydrogenase (LDH), pyruvate kinase (PYK), and enolase (ENO) brings about significant decrease in the glycolytic flux of cancer cells and accumulation of intermediate metabolites, mainly fructose-1,6-bisphosphate (Fru1,6BP), and dihydroxyacetone phosphate (DHAP), which are inhibitors of HK and HPI, respectively. Here it was found by kinetic modeling that inhibition of cancer glycolysis can be attained by blocking downstream non flux-controlling steps as long as Fru1,6BP and DHAP, regulatory metabolites of flux-controlling enzymes, are accumulated. Furthermore, experimental results and further modeling showed that oxamate and iodoacetate inhibitions of PYK, ENO, and glyceraldehyde3-phosphate dehydrogenase (GAPDH), but not of LDH and phosphoglycerate kinase, induced accumulation of Fru1,6BP and DHAP in AS-30D hepatoma cells. Indeed, PYK, ENO, and GAPDH exerted the highest control on the Fru1,6BP and DHAP concentrations. The high levels of these metabolites inhibited HK and HPI and led to glycolytic flux inhibition, ATP diminution, and accumulation of toxic methylglyoxal. Hence, the anticancer effects of downstream glycolytic inhibitors are very likely mediated by this mechanism. In parallel, it was also found that uncompetitive inhibition of the flux-controlling steps is a more potent mechanism than competitive and mixed-type inhibition to efficiently perturb cancer glycolysis.

• cancer glycolysis
• enolase inhibition
• feed-back inhibition
• metabolic regulation
• oxamate
• pyruvate kinase inhibition
• uncompetitive inhibition

• 3-bromopyruvate
• Cancer metabolism
• Cancer therapy
• Clinical studies
• Monocarboxylate transporter
• Tumor microenvironment

• FLT3/ITD
• Glycolysis
• Metabolic alterations
• Mitochondria
• TKI resistance

• 3-bromopyruvate
• colorectal cancer
• hexokinase II
• hypoglycaemia
• knockdown
• survival signalling

• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Line, Tumor
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Gene Expression Regulation, Enzymologic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Glucose/genetics
• Glucose/metabolism
• Hexokinase/biosynthesis
• Hexokinase/genetics
• Humans
• Phosphorylation/drug effects
• Phosphorylation/genetics
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Pyruvates/pharmacology

• Aerobic glycolysis
• Hepatocellular carcinoma
• Lactate
• Metabolic interventions
• Oxidative stress

• Chemosensitization
• Cisplatin
• Colorectal cancer
• ROS
• Sulfasalazine
• xCT

Muscle type of pyruvate kinase (PKM) is one of the key mediators of the Warburg effect and tumor metabolism. Due to alternative splicing, there are at least 12 known isoforms of the PKM gene, of which PKM1 and PKM2 are two major isoforms with only a 23 amino acid sequenced difference but quite different characteristics and functions. It was previously thought the isoform switch from PKM1 to PKM2 resulted in high PKM2 expression in tumors, providing a great advantage to tumor cells. However, this traditional view was challenged by two recent studies; one study claimed that this isoform switch does not occur during the Warburg effect; the other study asserted that the isoform switch is tissue-specific. Here, we re-analyzed the RNA sequencing data of 25 types of human tumors from The Cancer Genome Atlas Data Portal, and confirmed that PKM2 was the major isoform in the tumors and was highly elevated in addition to the entire PKM gene. We further demonstrated that the expression level of PKM1 significantly declined even though there was substantially increased expression of the entire PKM gene. The proportion of PKM1 in total transcript variants also significantly declined in tumors but the proportion of PKM2 did not change accordingly. Therefore, we conclude that the isoform switch of PKM1 does indeed occur, but it switches to other isoforms rather than PKM2. Considering the change in the expression levels of PKM1, PKM2 and the entire PKM gene, we propose that the upregulation of PKM2 is primarily due to elevated transcriptional levels of the entire PKM gene, instead of the isoform switch.

• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
• cancer
• mechanism
• posttranslational modification (PTM)
• regulation

• R01 CA151610 NCI NIH HHS