1-C Metabolism—Serine, Glycine, Folates—In Acute Myeloid Leukemia

Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Studies in hematological malignancies have shown alterations in fatty acid, folate, and amino acid metabolism pathways in cancer cells. One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. Glutamine depletion has also emerged as a therapeutic approach for cancers that have demonstrated dependence on glutamine for survival. Recent studies have shown that in response to glutamine deprivation leukemia cells upregulate key enzymes in the serine biosynthesis pathway, suggesting that serine upregulation may be a targetable compensatory mechanism. These new findings may provide opportunities for novel cancer treatments.

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NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21186799 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6799 ◽

Cited By ~ 1

Author(s):

Yoshiaki Sunami

Keyword(s):

Hepatocellular Carcinoma ◽

Lipid Metabolism ◽

Liver Diseases ◽

Primary Liver Cancer ◽

Tumor Development ◽

Lipid Synthesis ◽

Acid Synthesis ◽

Metabolic Reprogramming ◽

Acetate Metabolism ◽

Nonalcoholic Fatty Liver

Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

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DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.254 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii63-ii63

Author(s):

Lakshmi Bollu ◽

Derek Wainwright ◽

Lijie Zhai ◽

Erik Ladomersky ◽

Kristen Lauing ◽

...

Keyword(s):

Protein Degradation ◽

Time Course ◽

Immune Cell ◽

Enzyme Inhibitors ◽

Tumor Development ◽

Ubiquitin Proteasome System ◽

Degradation Pathway ◽

Specific Protein ◽

Cell Functions

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a specific protein and recruit an E3 ubiquitin ligase that enhance proteasome-mediated degradation of the target protein. METHODS A library of ≥100 IDO-PROTACs were developed by joining BMS986205 (IDO binder) with a linker group to various E3-ligase ligands. Western blot analysis of PROTAC-induced IDO degradation was tested in vitro among multiple human and mouse GBM cell lines including U87, GBM6, GBM43 and GL261 along a time course ranging between 1–96 hours of treatment and at varying concentrations. The mechanism of IDO protein degradation was investigated using pharmacologic ligands that inhibit or compete with the proteasome-mediated protein degradation pathway. RESULTS Primary screening identified several IDO-PROTACs with IDO protein degradation potential. Secondary screening showed that our lead compound has a DC50 value of ~0.5µM with an ability to degrade IDO in all GBM cells analyzed, and an initial activity within 12 hours of treatment that extended for up to 96 hours. Mutating the CRBN-binding ligand, pretreatment with the ubiquitin proteasome system inhibitors MG132 or MLN4924 or using unmodified parental compound all inhibited IDO protein degradation. CONCLUSIONS This study developed an initial IDO-PROTAC technology that upon further optimization, can neutralize both IDO enzyme and non-enzyme immunosuppressive effects. When combined with other forms of immunotherapy, IDO-PROTACs have the potential to substantially enhance immunotherapeutic efficacy in patients with GBM.

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Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

Cancer Gene Therapy ◽

10.1038/s41417-021-00326-4 ◽

2021 ◽

Author(s):

Tatsunori Suzuki ◽

Takahiro Kishikawa ◽

Tatsuyuki Sato ◽

Norihiko Takeda ◽

Yuki Sugiura ◽

...

Keyword(s):

Gene Mutation ◽

Biological Effects ◽

Redox Balance ◽

Metabolic Reprogramming ◽

Ductal Adenocarcinoma ◽

Early Event ◽

Autophagic Flux ◽

Nutritional Interventions ◽

Mutational Activation ◽

Almost All

AbstractMutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.

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Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽

10.3390/cells10040903 ◽

2021 ◽

Vol 10 (4) ◽

pp. 903

Author(s):

Xiao-Mei Zhang ◽

De-Gao Chen ◽

Shengwen Calvin Li ◽

Bo Zhu ◽

Zhong-Jun Li

Keyword(s):

Metabolic Regulation ◽

Transcriptional Profiling ◽

Tumor Development ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Functional Heterogeneity ◽

Tumor Associated Macrophages ◽

Metabolic Remodeling ◽

And Function ◽

Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

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Comprehensive Metabolomic Analysis Reveals Dynamic Metabolic Reprogramming in Hep3B Cells with Aflatoxin B1 Exposure

Toxins ◽

10.3390/toxins13060384 ◽

2021 ◽

Vol 13 (6) ◽

pp. 384

Author(s):

Shufeng Wang ◽

Xin Yang ◽

Feng Liu ◽

Xinzheng Wang ◽

Xuemin Zhang ◽

...

Keyword(s):

Aflatoxin B1 ◽

Drug Targets ◽

High Sensitivity ◽

Tca Cycle ◽

Acid Synthesis ◽

Metabolic Reprogramming ◽

Pyrimidine Metabolism ◽

Rapid Separation ◽

Hexosamine Pathway ◽

Hep3b Cells

Hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure have been recognized as independent risk factors for the occurrence and development of hepatocellular carcinoma (HCC), but their combined impacts and the potential metabolic mechanisms remain poorly characterized. Here, a comprehensive non-targeted metabolomic study was performed following AFB1 exposed to Hep3B cells at two different doses: 16 μM and 32 μM. The metabolites were identified and quantified by an ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based strategy. A total of 2679 metabolites were identified, and 392 differential metabolites were quantified among three groups. Pathway analysis indicated that dynamic metabolic reprogramming was induced by AFB1 and various pathways changed significantly, including purine and pyrimidine metabolism, hexosamine pathway and sialylation, fatty acid synthesis and oxidation, glycerophospholipid metabolism, tricarboxylic acid (TCA) cycle, glycolysis, and amino acid metabolism. To the best of our knowledge, the alteration of purine and pyrimidine metabolism and decrease of hexosamine pathways and sialylation with AFB1 exposure have not been reported. The results indicated that our metabolomic strategy is powerful to investigate the metabolome change of any stimulates due to its high sensitivity, high resolution, rapid separation, and good metabolome coverage. Besides, these findings provide an overview of the metabolic mechanisms of the AFB1 combined with HBV and new insight into the toxicological mechanism of AFB1. Thus, targeting these metabolic pathways may be an approach to prevent carcinogen-induced cancer, and these findings may provide potential drug targets for therapeutic intervention.

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Redox-Modulating Agents in the Treatment of Viral Infections

International Journal of Molecular Sciences ◽

10.3390/ijms21114084 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4084 ◽

Cited By ~ 6

Author(s):

Paola Checconi ◽

Marta De Angelis ◽

Maria Elena Marcocci ◽

Alessandra Fraternale ◽

Mauro Magnani ◽

...

Keyword(s):

Inflammatory Response ◽

Redox State ◽

Viral Infections ◽

Rna Virus ◽

Influenza Virus Infection ◽

Redox Balance ◽

Physiological Conditions ◽

Cell Functions ◽

Enzymatic Systems ◽

Strong Inflammatory Response

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.

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Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer

Cancers ◽

10.3390/cancers13112719 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2719

Author(s):

Alba Loras ◽

Cristina Segovia ◽

José Luis Ruiz-Cerdá

Keyword(s):

Bladder Cancer ◽

Cancer Biology ◽

Metabolic Regulation ◽

Tumor Development ◽

Dna Methyltransferases ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Oncogenic Signaling ◽

Invasive Approach ◽

Non Invasive

Bladder cancer (BC) represents a clinical, social, and economic challenge due to tumor-intrinsic characteristics, limitations of diagnostic techniques and a lack of personalized treatments. In the last decade, the use of liquid biopsy has grown as a non-invasive approach to characterize tumors. Moreover, the emergence of omics has increased our knowledge of cancer biology and identified critical BC biomarkers. The rewiring between epigenetics and metabolism has been closely linked to tumor phenotype. Chromatin remodelers interact with each other to control gene silencing in BC, but also with stress-inducible factors or oncogenic signaling cascades to regulate metabolic reprogramming towards glycolysis, the pentose phosphate pathway, and lipogenesis. Concurrently, one-carbon metabolism supplies methyl groups to histone and DNA methyltransferases, leading to the hypermethylation and silencing of suppressor genes in BC. Conversely, α-KG and acetyl-CoA enhance the activity of histone demethylases and acetyl transferases, increasing gene expression, while succinate and fumarate have an inhibitory role. This review is the first to analyze the interplay between epigenome, metabolome and cell signaling pathways in BC, and shows how their regulation contributes to tumor development and progression. Moreover, it summarizes non-invasive biomarkers that could be applied in clinical practice to improve diagnosis, monitoring, prognosis and the therapeutic options in BC.

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A standardized extract of Asparagus officinalis stem improves HSP70-mediated redox balance and cell functions in bovine cumulus-granulosa cells

Scientific Reports ◽

10.1038/s41598-021-97632-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Khoi Thieu Ho ◽

Kohei Homma ◽

Jun Takanari ◽

Hanako Bai ◽

Manabu Kawahara ◽

...

Keyword(s):

Cell Function ◽

Redox Balance ◽

Asparagus Officinalis ◽

Hsp70 Expression ◽

Ros Generation ◽

Cellular Redox ◽

Pheochromocytoma Cells ◽

Cell Functions ◽

Progesterone Synthesis ◽

Hsp70 Induction

AbstractHeat shock (HS) protein 70 (HSP70), a well-known HS-induced protein, acts as an intracellular chaperone to protect cells against stress conditions. Although HS induces HSP70 expression to confer stress resistance to cells, HS causes cell toxicity by increasing reactive oxygen species (ROS) levels. Recently, a standardized extract of Asparagus officinalis stem (EAS), produced from the byproduct of asparagus, has been shown to induce HSP70 expression without HS and regulate cellular redox balance in pheochromocytoma cells. However, the effects of EAS on reproductive cell function remain unknown. Here, we investigated the effect of EAS on HSP70 induction and oxidative redox balance in cultured bovine cumulus-granulosa (CG) cells. EAS significantly increased HSP70 expression; however, no effect was observed on HSP27 and HSP90 under non-HS conditions. EAS decreased ROS generation and DNA damage and increased glutathione (GSH) synthesis under both non-HS and HS conditions. Moreover, EAS synergistically increased HSP70 and HSF1 expression and increased progesterone levels in CG cells. Treatment with an HSP70 inhibitor significantly decreased GSH level, increased ROS level, and decreased HSF1, Nrf2, and Keap1 expression in the presence of EAS. Furthermore, EAS significantly increased progesterone synthesis. Thus, EAS improves HSP70-mediated redox balance and cell function in bovine CG cells.

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CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.167 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi43

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

Joseph Ippolito

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Male And Female ◽

Glutamine Deprivation ◽

Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

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Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20191920 ◽

2020 ◽

Vol 217 (8) ◽

Cited By ~ 4

Author(s):

Teresa Manzo ◽

Boone M. Prentice ◽

Kristin G. Anderson ◽

Ayush Raman ◽

Aislyn Schalck ◽

...

Keyword(s):

Fatty Acids ◽

T Cells ◽

Lipid Metabolism ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Metabolic Reprogramming ◽

Long Chain Fatty Acids ◽

Cell Functions ◽

Long Chain ◽

Chain Fatty Acids

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

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