bims-glucam 2021-08-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–08–01
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.
HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways.
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells.
Coordination of the Uptake and Metabolism of Amino Acids in Mycobacterium tuberculosis-Infected Macrophages.
Cadmium promotes glycolysis upregulation and glutamine dependency in human neuronal cells.
Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.
Glutamate-Oxaloacetate Transaminase 1 Impairs Glycolysis by Interacting with Pyruvate Carboxylase and Further Inhibits the Malignant Phenotypes of Glioblastoma Cells.
Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
Morpho-metabotyping the oxidative stress response.

Front Oncol. 2021 ;11 697894

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.

Guofeng Ma, Chun Li, Zhilei Zhang, Ye Liang, Zhijuan Liang, Yuanbin Chen, Liping Wang, Dan Li, Manqin Zeng, Wenhong Shan, Haitao Niu.

  Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

Keywords:  PD-1/PD-L1 immune checkpoint; combination therapy; glucose metabolism; glutamine metabolism; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.697894
Cancer Lett. 2021 Jul 22. pii: S0304-3835(21)00354-2. [Epub ahead of print]518 243-255

HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways.

Vasudevarao Penugurti, Saratchandra Singh Khumukcham, Chiranjeevi Padala, Anju Dwivedi, Karthik Reddy Kamireddy, Srinivasulu Mukta, Triveni Bhopal, Bramanandam Manavathi.

  While cancer cells rewire metabolic pathways to sustain growth and survival under metabolic stress in solid tumors, the molecular mechanisms underlying these processes remain largely unknown. In this study, cancer cells switched from survival to death during the early to late phases of metabolic stress by employing a novel signaling switch from AMP activated protein kinase (AMPK)-Forkhead box O3 (FOXO3a)-hematopoietic PBX1-interacting protein (HPIP) to the ring finger protein 2 (RNF2)-HPIP-ubiquitin (Ub) pathway. Acute metabolic stress induced proto-oncogene HPIP expression in an AMPK-FOXO3a-dependent manner in breast cancer (BC) cells. HPIP depletion reduced cell survival and tumor formation in mouse xenografts, which was accompanied by diminished intracellular ATP levels and increased apoptosis in BC cells in response to metabolic (glucose) stress. Glutamine flux (13C-labeled) analysis further suggested that HPIP rewired glutamine metabolism by controlling the expression of the solute carrier family 1 member 5 (SLC1A5) and glutaminase (GLS) genes by acting as a coactivator of MYC to ensure cell survival upon glucose deprivation. However, in response to chronic glucose stress, HPIP was ubiquitinated by the E3-Ub ligase, RNF2, and was concomitantly degraded by the proteasome-mediated pathway, ensuring apoptosis. In support of these data, clinical analyses further indicated that elevated levels of HPIP correlated with AMPK activation in BC. Taken together, these data suggest that HPIP is a signal coordinator during metabolic stress and thus serves as a potential therapeutic target in BC.

Keywords:  AMPK; Apoptosis; Cell survival; FOXO3a; Glutaminolysis; HPIP; MYC

DOI:  https://doi.org/10.1016/j.canlet.2021.07.027
Biochem Biophys Res Commun. 2021 Jul 26. pii: S0006-291X(21)01106-2. [Epub ahead of print]571 118-124

Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells.

Selahattin C Ozcan, Aydan Mutlu, Tugba H Altunok, Yunus Gurpinar, Aybike Sarioglu, Sabire Guler, Robertino J Muchut, Alberto A Iglesias, Serap Celikler, Paul M Campbell, Abdullah Yalcin.

  Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.

Keywords:  AZ PFKFB3 26; CB-839; GLS1; KRAS; PFKFB3; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.bbrc.2021.07.070
Front Immunol. 2021 ;12 711462

Coordination of the Uptake and Metabolism of Amino Acids in Mycobacterium tuberculosis-Infected Macrophages.

Qingkui Jiang, Lanbo Shi.

  Macrophage polarization to the M1-like phenotype, which is critical for the pro-inflammatory and antimicrobial responses of macrophages against intracellular pathogens, is associated with metabolic reprogramming to the Warburg effect and a high output of NO from increased expression of NOS2. However, there is limited understanding about the uptake and metabolism of other amino acids during M1 polarization. Based on functional analysis of a group of upregulated transporters and enzymes involved in the uptake and/or metabolism of amino acids in Mycobacterium tuberculosis-infected macrophages, plus studies of immune cell activation, we postulate a coherent scheme for amino acid uptake and metabolism during macrophage polarization to the M1-like phenotype. We describe potential mechanisms that the increased arginine metabolism by NOS2 is metabolically coupled with system L transporters LAT1 and LAT2 for the uptake of neutral amino acids, including those that drive mTORC1 signaling toward the M1-like phenotype. We also discuss the underappreciated pleiotropic roles of glutamine metabolism in the metabolic reprogramming of M1-like macrophages. Collectively, our analyses argue that a coordinated amino acid uptake and metabolism constitutes an integral component of the broad metabolic scheme required for macrophage polarization to M1-like phenotype against M. tuberculosis infection. This idea could stimulate future experimental efforts to elucidate the metabolic map of macrophage activation for the development of anti-tuberculosis therapies.

Keywords:  M1 polarization; Mycobacterium tuberculosis; amino acid transporters; arginine metabolism; glutaminolysis; immunometabolism; redox homeostasis; system L transporters

DOI:  https://doi.org/10.3389/fimmu.2021.711462
Neurochem Int. 2021 Jul 23. pii: S0197-0186(21)00190-X. [Epub ahead of print]149 105144

Cadmium promotes glycolysis upregulation and glutamine dependency in human neuronal cells.

Federica Bovio, Pasquale Melchioretto, Matilde Forcella, Paola Fusi, Chiara Urani.

  Cadmium is a widespread pollutant, which easily accumulates inside the human body with an estimated half-life of 25-30 years. Many data strongly suggest that it may play a role in the pathogenesis of neurodegenerative diseases. In this paper we investigated cadmium effect on human SH-SY5Y neuroblastoma cells metabolism. Results showed that, although SH-SY5Y cells already showed hyperactivated glycolysis, cadmium further increased basal glycolytic rate. Both glycolytic capacity and reserve were also increased following cadmium administration, endowing the cells with a higher compensatory glycolysis when oxidative phosphorylation was inhibited. Cadmium administration also led to an increase in glycolytic ATP production rate, paralleled by a decrease in ATP production by oxidative phosphorylation, due to an impairment of mitochondrial respiration. Moreover, following cadmium administration, mitochondria increased their dependency on glutamine, while decreasing lipids oxidation. On the whole, our data show that cadmium exacerbates the Warburg effect and promotes the use of glutamine as a substrate for lipid biosynthesis. Although increased glutamine consumption leads to an increase in glutathione level, this cannot efficiently counteract cadmium-induced oxidative stress, leading to membrane lipid peroxidation. Oxidative stress represents a serious threat for neuronal cells and our data confirm glutathione as a key defense mechanism.

Keywords:  Cadmium; Energy metabolism; Glutamine; Glutathione; Oxidative stress; SH-SY5Y neuronal cells

DOI:  https://doi.org/10.1016/j.neuint.2021.105144
Neoplasia. 2021 Jul 21. pii: S1476-5586(21)00046-4. [Epub ahead of print]23(9): 879-886

Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.

Douglas L Rothman, Robert G Shulman.

  Previously we suggested that the early Warburg effect can be explained by the use by cancer cells the glycogen shunt during a rapid increase in glucose concentration. In analogy to the Crabtree effect in yeast, the shunt plays a critical role in maintaining homeostasis of glycolytic intermediate levels during these transitions. We extend this analysis here, and propose that the recently appreciated flexibility of cancer cell glucose and glycogen metabolism involves 4 metabolic states that we recently identified in metabolic control analysis studies of yeast. Under stable conditions of low glucose and normal O2 yeast, and by analogy cancer, cells are in the Respiration State in which through gene expression for oxidizing non glucose substrates. When their environment changes to high glucose with reduced O2 levels, such as occur in tumors, they transition to the Glycolysis State due to gene expression of new glycolytic enzyme isoforms such as PKM2. These isoforms optimize metabolism to sustain the Warburg effect. When the changes in glucose and O2 levels are rapid there may be insufficient time for gene expression to adapt. The metabolic flexibility conferred by 2 states of the glycogen shunt allow the cells to survive these transitions. The model explains experimental observations in cancer such as the function of the glycogen shunt and the frequent expression of PKM2 in cells undergoing the Warburg Effect. A surprising conclusion is that the function of PKM2 is to maintain glycolytic intermediate homeostasis rather than controlling the glycolytic flux. The glycogen shunt may also have an important role in cancer metabolic reprogramming by allowing cancer cells to survive large glucose and oxygen changes during the selection of mutations that lead to the Warburg phenotype.

Keywords:  Glycogen Shunt; Homeostasis; Metabolic Flexibility; Oncogenesis; Warburg Effect

DOI:  https://doi.org/10.1016/j.neo.2021.06.004
World Neurosurg. 2021 Jul 26. pii: S1878-8750(21)01106-2. [Epub ahead of print]

Glutamate-Oxaloacetate Transaminase 1 Impairs Glycolysis by Interacting with Pyruvate Carboxylase and Further Inhibits the Malignant Phenotypes of Glioblastoma Cells.

Tianchi Tang, Yang Liu, Min Yang, Wanchun Zhu, Ming Tu, Ming Chen.

   BACKGROUND: Glycolysis is an important metabolic manner in glioblastoma multiforme (GBM)'s rapid growth. It has been reported that glutamate-oxaloacetate transaminase 1 (GOT1) is low-expressed in GBM and patients with high-expressed GOT1 have better prognosis. However, the effect and mechanism of GOT1 on glycolysis and malignant phenotypes of GBM cells are still unclear.
METHODS: The expression differences of GOT1 between GBM parenchyma and adjacent tissues were detected. The prognosis and clinical data with different levels of GOT1 were also analyzed. The change of glucose metabolism were measured by glucose consumption, production of lactate and pyruvate after GOT1 was knocked down or overexpressed. The effect of GOT1 on GBM cell's malignant phenotypes were analyzed by Western-blot, CCK-8 assay and flow cytometry. The relationship between GOT1 and pyruvate carboxylase (PC) was examined by immunoprecipitation and immunofluorescence.
RESULTS: GOT1 was low-expressed in GBM and patients with high-expressed GOT1 had longer survival period. Overexpressed GOT1 inhibited the glycolysis and malignant phenotypes of GBM cells. 2-DG treatment could partially reverse the enhancement of malignant phenotypes caused by knockdown of GOT1. The expression of GOT1 were positively correlated with PC. The inhibitory effect of GOT1 on glycolysis could be partially reversed by PC's knockdown.
CONCLUSIONS: GOT1 could impair the glycolysis by interacting with PC and further inhibit the malignant phenotypes of GBM cells.

Keywords:  glioblastoma multiforme; glutamate-oxaloacetate transaminase 1; glycolysis

DOI:  https://doi.org/10.1016/j.wneu.2021.07.097
EMBO J. 2021 Jul 26. e107336

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.

Rojyar Khezri, Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten.

  During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

Keywords:   Drosophila ; autophagy; cancer cachexia; muscle; tumor; wasting

DOI:  https://doi.org/10.15252/embj.2020107336
Sci Rep. 2021 Jul 29. 11(1): 15471

Morpho-metabotyping the oxidative stress response.

Mate Rusz, Giorgia Del Favero, Yasin El Abiead, Christopher Gerner, Bernhard K Keppler, Michael A Jakupec, Gunda Koellensperger.

Oxidative stress and reactive oxygen species (ROS) are central to many physiological and pathophysiological processes. However, due to multiple technical challenges, it is hard to capture a comprehensive readout of the cell, involving both biochemical and functional status. We addressed this problem by developing a fully parallelized workflow for metabolomics (providing absolute quantities for > 100 metabolites including TCA cycle, pentose phosphate pathway, purine metabolism, glutathione metabolism, cysteine and methionine metabolism, glycolysis and gluconeogenesis) and live cell imaging microscopy. The correlative imaging strategy was applied to study morphological and metabolic adaptation of cancer cells upon short-term hydrogen peroxide (H2O2) exposure in vitro. The combination provided rich metabolic information at the endpoint of exposure together with imaging of mitochondrial effects. As a response, superoxide concentrations were elevated with a strong mitochondrial localization, and multi-parametric image analysis revealed a shift towards fragmentation. In line with this, metabolism reflected both the impaired mitochondrial function and shifts to support the first-line cellular defense and compensate for energy loss. The presented workflow combining high-end technologies demonstrates the applicability for the study of short-term oxidative stress, but it can be suitable for the in-depth study of various short-term oxidative and other cellular stress-related phenomena.

DOI: https://doi.org/10.1038/s41598-021-94585-8