Function Of Metabolic Enzymes Research Articles

The 150 most important questions in cancer research and clinical oncology series: questions 102–104

To accelerate our endeavors to overcome cancer, Visualized Cancer Medicine continues the previously launched program of publishing the 150 most important questions in cancer research and clinical oncology. In this article, three more questions are presented as follows: Question 102: Can non-glucose-based tumor imaging techniques facilitate tumor detection and metabolic classification? Question 103: how can we develop medicines to inhibit the cancer-specific metabolic functions of metabolic enzymes in tumors expressing wild-type IDH, without interfering with their canonical catalytic activities? Question 104: Can dietary-based cancer therapy be proven effective in treating cancer?

Identifying hepatoprotective mechanism and effective components of Yinchenzhufu decoction in chronic cholestatic liver injury using a comprehensive strategy based on metabolomics, molecular biology, pharmacokinetics, and cytology

Ethnopharmacological relevanceIn Traditional Chinese Medicine (TCM), cholestasis liver disease belongs to jaundice. Yinchenzhufu decoction (YCZFD) is a classic formula used for treating jaundice. Aim of the studyThis study was aimed to investigate the potential mechanism and effective components of YCZFD in chronic cholestatic liver injury (CCLI). Materials and methodsA chronic cholestatic mouse model induced by 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine was used to investigate the effect of YCZFD. Then, metabolomics was used to investigate the metabolites influenced by YCZFD. Serum and liver bile acid (BA) levels were measured using liquid chromatography coupled with triple quadruple mass spectrometry (LC-MS/MS), and the gene and protein expressions of BA transporters and metabolic enzymes were detected. Additionally, the pharmacokinetics of multiple components of YCZFD was explored to clarify the potential effective components. The effects of absorbed components of YCZFD on BA metabolism and transporter function, inflammation, and farnesoid X receptor (FXR) and pregnane X receptor (PXR) activation were analyzed using sandwich cultured rat hepatocytes, AML12 cells, and dual-luciferase receptor systems, respectively. ResultsYCZFD decreased the liver damage in chronic cholestatic mice. Serum metabolomics results indicated that the main pathways influenced by YCZFD involved primary BA biosynthesis and arachidonic acid metabolism. YCZFD upregulated the expression of FXR, PXR, and BA efflux transporters and the metabolic enzymes of liver tissues, promoting BA excretion and metabolism in cholestatic mice. Additionally, YCZFD downregulated the expression of genes and proteins of the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and decreased liver inflammation. The pharmacokinetic study indicated that multiple components showed different pharmacokinetic properties. Among the absorbed components of YCZFD, multiple components activated the transcription of FXR and PXR, regulated BA transporters and metabolic enzyme function, and reduced the gene expression of TLR4 and NF-κB1. ConclusionYCZFD can ameliorate CCLI by promoting the excretion and metabolism of BAs and inhibiting inflammation via the TLR4/NF-κB signaling pathway. The multiple components of YCZFD could act on BA homeostasis regulation and anti-inflammation, exhibiting a combined effect against CCLI.

Widespread, Reversible Cysteine Modification by Methylglyoxal Regulates Metabolic Enzyme Function.

Methylglyoxal (MGO), a reactive metabolite byproduct of glucose metabolism, is known to form a variety of posttranslational modifications (PTMs) on nucleophilic amino acids. For example, cysteine, the most nucleophilic proteinogenic amino acid, forms reversible hemithioacetal and stable mercaptomethylimidazole adducts with MGO. The high reactivity of cysteine toward MGO and the rate of formation of such modifications provide the opportunity for mechanisms by which proteins and pathways might rapidly sense and respond to alterations in levels of MGO. This indirect measure of alterations in glycolytic flux would thereby allow disparate cellular processes to dynamically respond to changes in nutrient availability and utilization. Here we report the use of quantitative LC-MS/MS-based chemoproteomic profiling approaches with a cysteine-reactive probe to map the proteome-wide landscape of MGO modification of cysteine residues. This approach led to the identification of many sites of potential functional regulation by MGO. We further characterized the role that such modifications have in a catalytic cysteine residue in a key metabolic enzyme and the resulting effects on cellular metabolism.

Enhancement and maintenance of hepatic metabolic functions by controlling 3D aggregation of cryopreserved human iPS cell-derived hepatocyte-like cells

Hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells are potent cells to study individual-specific hepatotoxicity for drug screening test. However, the functions of metabolic enzymes are practically low. Here, we reconstituted stable and compact 3D spheroids of commercially available cryopreserved HLCs by our original spheroid formation method with high viscous methylcellulose medium. 3D formation enhanced the hepatic functions and maintained the functions for 14 days. Especially, the expression of cytochrome P450s was 10- to 100-fold enhanced compared to conventional 2D culture, which is applicable to a typical drug-metabolizing test using liquid chromatograph-tandem mass spectrometer. In conclusion, we successfully formed human HLC spheroid from commercially available cryo-preserved cells, which realized remarkable hepatic maturation by prolonged 3D culture, especially in terms of drug-metabolizing enzymes. Our spheroid formation technology has the potential to make HLC spheroids a potent tool in aspects of pharmaceutical research, such as drug screening and pharmacokinetic studies.

Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients.

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019-1.900); p = 0.038] but not from apixaban (p = 0.487). Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.

Abstract 14063: Eight Pharmacokinetic-Related Genetic Variants Were Not Associated With Bleeding From Direct Oral Anticoagulants in Non-Valvular Atrial Fibrillation Patients

Background. Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing stroke risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy in non-valvular AF since they are as effective and safer than warfarin. Although patients bleed less overall from DOACs, bleeding still is the main safety concern with this therapy. Previous studies have shown that genetic variants modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs, which then affect DOAC plasma concentrations. However, whether those functional PK genetic variants are significantly associated with the risk of bleeding on DOACs is unknown. Aim. Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. Methods. A retrospective cohort study was carried out with 2,364 Caucasians with non-valvular AF and treated with rivaroxaban or apixaban. Patients were genotyped as part of the genomic biobank at the University of Michigan Health System. The primary endpoint was a composite of major and clinically relevant non-major (CRNM) bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of 8 SNVs in 5 PK genes ( ABCB1 , ABCG2 , CYP3A4 , CYP3A5 , CYP2J2 ) with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. Six tests were performed as 3 of the SNVs are in the same haplotype. P-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results. A total of 412 (17.4%) major and CRNM bleeding events occurred over 2.27 ± 2.03 years of follow-up. None of the PK SNVs were significantly associated with bleeding risk on DOACs (Table 1). Conclusion. SNVs that affect the function of PK genes were not significantly associated with major and CRNM bleeding from rivaroxaban or apixaban in 2,364 AF patients.

YiaC and CobB regulate lysine lactylation in Escherichia coli

Lysine lactylation (Kla) has recently been reported to participate in regulating transcription in human cells. However, the characterization, regulatory mechanism and functional consequence of Kla in prokaryotes remain unclear. Here, we report that YiaC functions as a lysine lactylase and that CobB serves as a lysine delactylase in the regulation of metabolism. We demonstrate that YiaC catalyzes the addition of Kla, while CobB erases this PTM both in vitro and intracellularly. Moreover, we show that YdiF can catalyze the formation of a lactyl-coenzyme A, which donates lactyl group for Kla. Quantitative proteomic analysis further reveals 446 endogenous Kla sites targeted by CobB and 79 candidates targeted by YiaC in Escherichia coli (E. coli). Furthermore, we present that Kla can influence the functions of metabolic enzymes. Interestingly, we demonstrate that CobB can specifically modulate the activity of PykF by regulating K382la, promoting glycolysis and bacterial growth. Our study identifies the regulatory enzymes and functional network of Kla and reveals a Kla-mediated molecular mechanism catalyzed by CobB for glycolysis regulation in E. coli.

A Cancer Cell-Intrinsic GOT2-PPARδ Axis Suppresses Antitumor Immunity.

Prior studies demonstrate the important moonlighting functions of metabolic enzymes in cancer. We find that the mitochondrial transaminase GOT2 binds directly to fatty acid ligands that regulate the nuclear receptor PPARδ, and this functional interaction critically regulates the immune microenvironment of pancreatic cancer to promote tumor progression. See related commentary by Nwosu and di Magliano, p. 2237.. This article is highlighted in the In This Issue feature, p. 2221.

The role and mechanism of noncoding RNAs in regulation of metabolic reprogramming in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Metabolic reprogramming is considered to be an important hallmark of cancer. Emerging studies have demonstrated that noncoding RNAs (ncRNAs) are closely associated with metabolic reprogramming of HCC. NcRNAs can directly regulate the expressions or functions of metabolic enzymes or indirectly regulate the metabolism of HCC cells through some vital signaling pathways. Until now, the mechanisms of HCC development and progression remain largely unclear, and understanding the regulatory mechanism of ncRNAs on metabolic reprogramming of HCC may provide an important basis for breakthrough progress in the treatment of HCC. In this review, we summarize the ncRNAs involved in regulating metabolic reprogramming of HCC. Specifically, the regulatory roles of ncRNAs in glucose, lipid and amino acid metabolism are elaborated. In addition, we discuss the molecular mechanism of ncRNAs in regulation of metabolic reprogramming and possible therapeutic strategies that target the metabolism of cancer cells by modulating the expressions of specific ncRNAs.

Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα–FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

Cancer metabolism and tumor microenvironment: fostering each other?

The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.

Impact of metal nanoparticles on the structure and function of metabolic enzymes

The widespread use of nanoparticles raises many serious concerns about the safety and environmental impact of nanoparticles. Therefore, risk assessments of specific nanoparticles in occupational and environmental exposure are essential before their large-scale production and applications, especially in medicine and for usage in household items. In this study, the effects of five different metal nanoparticles on the structure, stability, and function of four metabolic enzymes were evaluated using various biophysical techniques. Our results show that Cu nanoparticles exhibited the most significant adverse effects on the structures, stability, and activities of all the metabolic enzymes. Zn nanoparticles caused moderate adverse effects on these enzymes. The rest of the metal (Al, Fe, and Ni) nanoparticles had a relatively lower impact on the metabolic enzymes. Our data indicated that Cu nanoparticles promote metal-catalyzed disulfide bond formation in these proteins. In summary, some metal nanoparticles can cause adverse effects on the structure, function, and stability of metabolic enzymes. In addition, metal nanoparticles may affect protein homeostasis in the cytosol or extracellular fluids.

The Non-canonical Role of Metabolic Enzymes in Immune Cells and Its Impact on Diseases

This review aims to elucidate the new functions of metabolic enzymes and how they impact and modulate the activation and differentiation of immune cells. Macrophages and T cells are components of the innate and adaptive immune systems and play an important role in several diseases. To perform their function, these cells undergo activation and differentiation. It is appreciated that immune cells concurrently reprogram their metabolism of glucose, amino acid, and fatty acid to generate energy and substances essential to perform their function. It was recently described that some metabolism-involved enzymes have unconventional functions upon immune cells. For instance, hexokinase can act as a sensor for bacterial antigens and, in some cases, activate inflammasome assembly. On the other hand, GAPDH and PKM2 regulate the expression of some cytokines, whereas LDH-A blocks the inflammatory response and stearoyl-CoA desaturase promotes the survival of the immune cells. Here, we summarize the recent findings of the non-canonical role of metabolism-related enzymes, mainly in glycolysis, since the influence of these little-known functions in immune cells and immune-mediated diseases is still a focus of recent works. Understanding and appreciating these enzymes and their mechanisms of action may assist in the development of new therapeutic strategies for autoimmunity, cancer, and transplantation.

Abstract 4933: Nuclear Pyruvate Kinase M2 (PKM2) contributes to PSAT1-mediated cell migration in EGFR-activated lung cancer cells

Abstract Increased activity of the serine synthesis pathway (SSP) has been demonstrated in many types of cancer and can contribute to tumor growth by providing precursors for numerous anabolic reactions. Lung cancer, which is the leading cause of cancer deaths in the U.S., is one of several tumor types displaying increased expression of enzymes within the SSP, particularly PSAT1 (phosphoserine aminotransferase 1). Furthermore, increased PSAT1 expression correlates with poorer overall survival in lung cancer patients. Several previous studies have demonstrated a requirement for PSAT1 for NSCLC proliferation and lung cancer growth. Yet, understanding the complete mechanism by which PSAT1 promotes lung cancer progression requires further investigation, particularly as serine can be imported from the extracellular environment. Recent discoveries of the non-canonical functions of metabolic enzymes in tumorigenesis prompted us to explore a plausible additional function of PSAT1 that may be contributing to lung tumorigenesis. Therefore, we investigated potential PSAT1 protein-protein interactions via GST pulldown assay with mass spectrometry (MS). Among the identified peptides, PKM2 was chosen for further study due to its prior functional link to serine metabolism. In vitro co-immunoprecipitation data showed that PSAT1 interacted selectively with PKM2, but not PKM1 and site-directed mutagenesis analysis found the contribution of the PKM2-specific exon in the interaction. Although in vitro assays found that PSAT1 enhanced the kinase function of recombinant PKM2, depletion of PSAT1 by shRNA did not alter the pyruvate kinase activity and expression in NSCLC cells. Recent reports implicating EGF-induced nuclear PKM2 function in transcription led us to study the role of PSAT1 in nuclear localization of PKM2 in EGFR-activated lung cancer cells. Cell fractionation studies demonstrated that silencing of PSAT1 in EGFR-mutant PC9 or EGF-stimulated A549 cells decreased PKM2 nuclear translocation. Further, PSAT1 suppression abrogated cell migration in EGFR-mutant PC9 and EGF stimulated A549. To further elucidate the role of nuclear PKM2, we introduced PKM2 variants tagged with a nuclear localization signal (NLS) into PSAT1 silenced PC9 cells. We found that re-expression of NLS-PKM2 acetyl-mimetic mutant, but not wild-type, partially restored the cell migration in PSAT1 silenced PC9 cells. Taken together, our findings suggested that PSAT1 contributes to EGFR-driven lung cancer cell migration in part through promoting nuclear PKM2 translocation and function. Citation Format: Rumeysa Biyik-Sit, Traci Kruer, Susan M. Dougherty, James Bradley, Michael L. Merchant, John O. Trent, Brian F. Clem. Nuclear Pyruvate Kinase M2 (PKM2) contributes to PSAT1-mediated cell migration in EGFR-activated lung cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4933.

Moonlighting Metabolic Enzymes in Cancer: New Perspectives on the Redox Code.

Significance: Metabolic reprogramming is considered to be a critical adaptive biological event that fulfills the energy and biomass demands for cancer cells. One hallmark of metabolic reprogramming is reduced oxidative phosphorylation and enhanced aerobic glycolysis. Such metabolic abnormalities contribute to the accumulation of reactive oxygen species (ROS), the by-products of metabolic pathways. Emerging evidence suggests that ROS can in turn directly or indirectly affect the expression, activity, or subcellular localization of metabolic enzymes, contributing to the moonlighting functions outside of their primary roles. This review summarizes the multifunctions of metabolic enzymes and the involved redox modification patterns, which further reveal the inherent connection between metabolism and cellular redox state. Recent Advances: These noncanonical functions of metabolic enzymes involve the regulation of epigenetic modifications, gene transcription, post-translational modification, cellular antioxidant capacity, and many other fundamental cellular events. The multifunctional properties of metabolic enzymes further expand the metabolic dependencies of cancer cells, and confer cancer cells with a means of adapting to diverse environmental stimuli. Critical Issues: Deciphering the redox-manipulated mechanisms with specific emphasis on the moonlighting function of metabolic enzymes is important for clarifying the pertinence between metabolism and redox processes. Future Directions: Investigation of the redox-regulated moonlighting functions of metabolic enzymes will shed new lights into the mechanism by which metabolic enzymes gain noncanonical functions, and yield new insights into the development of novel therapeutic strategies for cancer treatment by targeting metabolic-redox abnormalities. Antioxid. Redox Signal. 34, 979-1003.

Metabolic alterations in the tumor microenvironment and their role in oncogenesis.

Metabolic reprogramming is a characteristic feature of both cancer cells and their neighbouring cells in the tumor microenvironment (TME). The latter include stroma fibroblasts and adipocytes, that respectively differentiate to become cancer associated fibroblasts (CAFs) and cancer associated adipocytes (CAAs), and infiltrated immune cells, that collaborate with the stromal cells to provide the tumor a pro-tumorigenic niche. Here we discuss the association between the reprogramming of glucose metabolism in the TME and oncogenic signaling and its reflection in the non-canonical functions of metabolic enzymes. We also discuss the non-canonical actions of oncometabolites and the contribution to oncogenesis of external metabolites that accumulate in the TME as result of crosstalk between the tumor and the TME. Special emphasis is given in this regard to lysophosphatidic acid (LPA) and adenosine, two powerful metabolites, the concentrations of which rise in the TME due to altered metabolism of the tumor and its surrounding cells, allowing their action as external signals.

RETRACTED ARTICLE: Acetyl-CoA synthetase 3 promotes bladder cancer cell growth under metabolic stress

Cancer cells adapt to nutrient-deprived tumor microenvironment during progression via regulating the level and function of metabolic enzymes. Acetyl-coenzyme A (AcCoA) is a key metabolic intermediate that is crucial for cancer cell metabolism, especially under metabolic stress. It is of special significance to decipher the role acetyl-CoA synthetase short chain family (ACSS) in cancer cells confronting metabolic stress. Here we analyzed the generation of lipogenic AcCoA in bladder cancer cells under metabolic stress and found that in bladder urothelial carcinoma (BLCA) cells, the proportion of lipogenic AcCoA generated from glucose were largely reduced under metabolic stress. Our results revealed that ACSS3 was responsible for lipogenic AcCoA synthesis in BLCA cells under metabolic stress. Interestingly, we found that ACSS3 was required for acetate utilization and histone acetylation. Moreover, our data illustrated that ACSS3 promoted BLCA cell growth. In addition, through analyzing clinical samples, we found that both mRNA and protein levels of ACSS3 were dramatically upregulated in BLCA samples in comparison with adjacent controls and BLCA patients with lower ACSS3 expression were entitled with longer overall survival. Our data revealed an oncogenic role of ACSS3 via regulating AcCoA generation in BLCA and provided a promising target in metabolic pathway for BLCA treatment.

Proceedings of the 3rd International Conference for Cancer Metabolism and Therapy, October 12-14, 2018, Shanghai, China.

The 3rd International Conference for Cancer Metabolism and Therapy was successfully held at the South Hospital Conference Center of Shanghai First People's Hospital, nearly 200 international experts from the field of cancer metabolism and therapy and about two thousand local scientists attended the conference. The conference was sponsored by the Yangtze River Delta City Group Hospital Synergistic Development Strategic Alliance, the China Anti-Cancer Association Cancer Metabolism Professional Committee, the Chinese Association for Cancer Metabolism and Therapy under Chinese Medical Doctoral Association-Clinical Precision Medicine, and co-organized by the First People's Hospital Affiliated to Shanghai Jiaotong University, and Shanghai Jiao Tong University School of Basic Medicine Undertake, Translational Medicine Network, Shanghai Anti-Cancer Association Youth Council, Fudan University Affiliated Tumor Hospital, University of California, Los Angeles, Agi Hirshberg Center for Pancreatic Diseases and Hirshberg Foundation for Pancreatic Cancer Research, Dalian University of Technology, New York-Presbyterian, American Cancer Research Association (AACR). The theme of the conference was "Inheritance, Innovation, Excellence, Leading" and its aim is to create a high-end academic exchange platform to discuss new technologies, new methods, and new products in tumor metabolism, tumor immunity, tumor markers and other fields. The conference involves cancer metabolism reprogramming, metabolism and tumor microenvironment, lipid metabolism, non-metabolic function of metabolic enzymes, metabolism and epigenetics, clinical transformation, new technologies for tumor immunotherapy, clinical application of tumor immunotherapy, emerging targeted therapy, PD-1/PD-L1 technology, CAR-T technology, novel tumor protein markers, novel tumor methylation markers, ctDNA, CTC, etc. The meeting ended in a lively discussion among scientists from different levels who truly benefit from the sessions about cancer metabolism and treatment. The next meeting is planned to be held October 2 through October 6, 2019 in Los Angeles, Calif. The meeting venue will be announced accordingly in the meeting web site (www.cmt.org).

The potential of lipid soluble thiamine in the treatment of cancer

The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose, as well as micronutrients functioning as enzyme cofactors is required. The majority of co-enzymes are derivatives of water-soluble vitamins such as niacin, folate, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is under-appreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this hypothesis discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells.