bims-glucam 2021-09-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–09–26
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

SnapShot: Cancer metabolism.
A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.
Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.
Moonlighting functions of metabolic enzymes and metabolites in cancer.
Comprehensive Interrogation of Metabolic and Bioenergetic Responses of Early-Staged Zebrafish (Danio rerio) to a Commercial Copper Hydroxide Nanopesticide.
Glucose Metabolism and Glucose Transporters in Breast Cancer.
Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.
Warburg and pasteur phenotypes modulate cancer behavior and therapy.
Supply and demand: Cellular nutrient uptake and exchange in cancer.
Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.
Mitochondrial-derived compartments facilitate cellular adaptation to amino acid stress.

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00501-3. [Epub ahead of print]81(18): 3878-3878.e1

SnapShot: Cancer metabolism.

Julia S Brunner, Lydia W S Finley.

Metabolic networks support cancer cell survival, proliferation, and malignant progression. Cancer cells take up large amounts of nutrients such as glucose and glutamine whose metabolism provides the energy, reducing equivalents, and biosynthetic precursors required to meet the biosynthetic demands of proliferation. Intermediates of glycolysis and the tricarboxylic acid (TCA) cycle provide critical building blocks for synthesis of non-essential amino acids, nucleotides, and fatty acids. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2021.06.021
Immunother Adv. 2021 Jan;1(1): ltab010

A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.

Laura J Pallett, Sarah Dimeloe, Linda V Sinclair, Adam J Byrne, Anna Schurich.

  Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.

Keywords:  T cells; cancer immunotherapy; glutamine

DOI:  https://doi.org/10.1093/immadv/ltab010
Cancer Lett. 2021 Sep 20. pii: S0304-3835(21)00471-7. [Epub ahead of print]522 129-141

Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.

Keita Hanada, Kenji Kawada, Gen Nishikawa, Kosuke Toda, Hisatsugu Maekawa, Yasuyo Nishikawa, Hideyuki Masui, Wataru Hirata, Michio Okamoto, Yoshiyuki Kiyasu, Shusaku Honma, Ryotaro Ogawa, Rei Mizuno, Yoshiro Itatani, Hiroyuki Miyoshi, Takehiko Sasazuki, Senji Shirasawa, M Mark Taketo, Kazutaka Obama, Yoshiharu Sakai.

  Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes. Recent studies have revealed macropinocytosis's important role in metabolic adaptation to nutrient stress in cancer cells harboring KRAS mutations. Here we showed that KRAS-mutant CRC cells enhanced macropinocytosis for tumor growth under nutrient-depleted conditions. We also demonstrated that activation of Rac1 and phosphoinositide 3-kinase were involved in macropinocytosis of KRAS-mutant CRC cells. Furthermore, we found that macropinocytosis was closely correlated with asparagine metabolism. In KRAS-mutant CRC cells engineered with knockdown of asparagine synthetase, macropinocytosis was accelerated under glutamine-depleted condition, and albumin addition could restore the glutamine depletion-induced growth suppression by recovering the intracellular asparagine level. Finally, we discovered that the combination of macropinocytosis inhibition and asparagine depletion dramatically suppressed the tumor growth of KRAS-mutant CRC cells in vivo. These results indicate that dual blockade of macropinocytosis and asparagine bioavailability could be a novel therapeutic strategy for KRAS-mutant cancers.

Keywords:  Asparagine synthetase; KRAS mutation; Macropinocytosis; l-asparaginase

DOI:  https://doi.org/10.1016/j.canlet.2021.09.023
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00698-5. [Epub ahead of print]81(18): 3760-3774

Moonlighting functions of metabolic enzymes and metabolites in cancer.

Chaoyun Pan, Bo Li, M Celeste Simon.

The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor non-canonical ("moonlighting") functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.

DOI: https://doi.org/10.1016/j.molcel.2021.08.031
Environ Sci Technol. 2021 Sep 23.

Comprehensive Interrogation of Metabolic and Bioenergetic Responses of Early-Staged Zebrafish (Danio rerio) to a Commercial Copper Hydroxide Nanopesticide.

Xiaohong Wang, Yingju Qin, Xiaoyu Li, Bing Yan, Christopher J Martyniuk.

  The use of copper hydroxide nanopesticide can pose exposure risks to aquatic organisms. In this study, the toxicity of a copper hydroxide nanopesticide, compared to conventional copper sulfate at environmentally relevant doses, was evaluated using metabolomics and bioenergetic assays in embryonic zebrafish. At a copper concentration of 100 μg/L, the nanopesticide caused higher mortality and deformity compared to copper ions alone; despite higher copper accumulation, increased metallothionein and elevated ATP-binding cassette (ABC) transporter activity in zebrafish exposed to copper ions were observed. Both nanopesticide and copper ions reduced the abundance of metabolites of glycolysis and induced energetic stress in zebrafish. The nanopesticide also increased concentrations of several organic acids involved in the tricarboxylic acid (TCA) cycle and elevated the activity of isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, suggesting enhanced TCA cycle activity. Nanopesticide exposure depleted both glutamate and glutamine parallel to the upregulation of the TCA cycle. In addition, zebrafish exposed to the nanopesticide appeared to shift metabolism toward amino acid catabolism and lipid accumulation based upon altered expression profiles of glutaminase, glutamate dehydrogenase, fatty acid synthase, and acetyl-CoA carboxylase. Lastly, the ability of the ions to increase oxidative phosphorylation to alleviate energetic stress was reduced in the case of the nanopesticide. We hypothesize that, unlike copper ions alone, the nanopesticide induces higher toxicity to zebrafish because of increased protein catabolism. This study provides a comprehensive understanding of the risks of copper hydroxide nanopesticide exposure in relation to metabolic activity and mitochondrial function.

Keywords:  bioenergetic response; copper hydroxide nanopesticide; glycolysis; metabolic response; mitochondria; oxidative phosphorylation; tricarboxylic acid cycle; zebrafish

DOI:  https://doi.org/10.1021/acs.est.1c04431
Front Cell Dev Biol. 2021 ;9 728759

Glucose Metabolism and Glucose Transporters in Breast Cancer.

Eunah Shin, Ja Seung Koo.

  Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.

Keywords:  breast cancer; glucose metabolism; glucose transporter; pentose phosphate pathway; serine/glycine pathway

DOI:  https://doi.org/10.3389/fcell.2021.728759
Cancer Metab. 2021 Sep 23. 9(1): 33

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.

Kasey R Cargill, C Allison Stewart, Elizabeth M Park, Kavya Ramkumar, Carl M Gay, Robert J Cardnell, Qi Wang, Lixia Diao, Li Shen, You-Hong Fan, Wai Kin Chan, Philip L Lorenzi, Trudy G Oliver, Jing Wang, Lauren A Byers.

   INTRODUCTION: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.
METHODS: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.
RESULTS: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.
CONCLUSIONS: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

Keywords:  Glycolysis; MYC; Metabolism; PFK158; Small cell lung cancer

DOI:  https://doi.org/10.1186/s40170-021-00270-9
Anticancer Drugs. 2021 Sep 17.

Warburg and pasteur phenotypes modulate cancer behavior and therapy.

Caner Karaca, Atilla Tokatli, Anja Tokatli, Aslihan Karadag, Gizem Calibasi-Kocal.

Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation. Moreover, they support the synthesis of various biomolecules employed in growth and survival over branching pathways. Yet, cellular energetics are often misguided in cancers as a result of the mutations and altered signaling. As nontransformed and Pasteur-like cells metabolize glucose through oxidative respiration when only oxygen is sufficient, some cancer cells bypass this metabolic switch and run glycolysis at higher rates even in the presence of oxygen. The phenomenon is called aerobic glycolysis or the Warburg effect. An increasing number of studies indicate that both Warburg and Pasteur phenotypes are recognized in the cancer microenvironment and take vital roles in the regulation of drug resistance mechanisms such as redox homeostasis, apoptosis and autophagy. Therefore, the different phenotypes call for different therapeutic approaches. Combined therapies targeting energy metabolism grant new opportunities to overcome the challenges. Nevertheless, new biomarkers emerge to classify the energetic subtypes, thereby the cancer therapy, as our knowledge in coupling energy metabolism with cancer behavior grows.

DOI: https://doi.org/10.1097/CAD.0000000000001236
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00693-6. [Epub ahead of print]81(18): 3731-3748

Supply and demand: Cellular nutrient uptake and exchange in cancer.

Vasileios Papalazarou, Oliver D K Maddocks.

  Nutrient supply and demand delineate cell behavior in health and disease. Mammalian cells have developed multiple strategies to secure the necessary nutrients that fuel their metabolic needs. This is more evident upon disruption of homeostasis in conditions such as cancer, when cells display high proliferation rates in energetically challenging conditions where nutritional sources may be scarce. Here, we summarize the main routes of nutrient acquisition that fuel mammalian cells and their implications in tumorigenesis. We argue that the molecular mechanisms of nutrient acquisition not only tip the balance between nutrient supply and demand but also determine cell behavior upon nutrient limitation and energetic stress and contribute to nutrient partitioning and metabolic coordination between different cell types in inflamed or tumorigenic environments.

Keywords:  SLC proteins; amino acid; cancer; nutrient scavenging; nutrient transport; nutrient transporters

DOI:  https://doi.org/10.1016/j.molcel.2021.08.026
Cancer Control. 2021 Jan-Dec;28:28 10732748211041243

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.

Karolina Kozal, Paweł Jóźwiak, Anna Krześlak.

  In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

Keywords:  aerobic glycolysis; anti-cancer therapy; glucose transporters; hypoxia-inducible factor; inhibitors; lactate dehydrogenase; monocarboxylate transporters; pyruvate kinase

DOI:  https://doi.org/10.1177/10732748211041243
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00688-2. [Epub ahead of print]81(18): 3786-3802.e13

Mitochondrial-derived compartments facilitate cellular adaptation to amino acid stress.

Max-Hinderk Schuler, Alyssa M English, Tianyao Xiao, Thane J Campbell, Janet M Shaw, Adam L Hughes.

  Amino acids are essential building blocks of life. However, increasing evidence suggests that elevated amino acids cause cellular toxicity associated with numerous metabolic disorders. How cells cope with elevated amino acids remains poorly understood. Here, we show that a previously identified cellular structure, the mitochondrial-derived compartment (MDC), functions to protect cells from amino acid stress. In response to amino acid elevation, MDCs are generated from mitochondria, where they selectively sequester and deplete SLC25A nutrient carriers and their associated import receptor Tom70 from the organelle. Generation of MDCs promotes amino acid catabolism, and their formation occurs simultaneously with transporter removal at the plasma membrane via the multivesicular body (MVB) pathway. The combined loss of vacuolar amino acid storage, MVBs, and MDCs renders cells sensitive to high amino acid stress. Thus, we propose that MDCs operate as part of a coordinated cell network that facilitates amino acid homeostasis through post-translational nutrient transporter remodeling.

Keywords:  MDC; Tom70; amino acid; lysosome; mitochondria; nutrient carrier; vacuole

DOI:  https://doi.org/10.1016/j.molcel.2021.08.021