bims-glucam 2022-04-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–04–10
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.
Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.
Metabolic Reservoir Cycles in Cancer.
Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.
Metabolic Intervention Nanoparticles for triple-negative Breast Cancer Therapy Via Overcoming FSP1-mediated Ferroptosis Resistance.
In Situ Analysis of mTORC1/C2 and Metabolism-Related Proteins in Pediatric Osteosarcoma.
Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.
Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.
Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study.

Mol Cell. 2022 Mar 25. pii: S1097-2765(22)00254-4. [Epub ahead of print]

Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.

Bin Jiang, Jia Zhang, Guohui Zhao, Mengjue Liu, Jielu Hu, Furong Lin, Jinyang Wang, Wentao Zhao, Huanhuan Ma, Cixiong Zhang, Caiming Wu, Luming Yao, Qingfeng Liu, Xin Chen, Yating Cao, Yi Zheng, Chensong Zhang, Aidong Han, Donghai Lin, Qinxi Li.

  GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of cancer types. Here, we show that GLS1 facilitates apoptosis when glutamine is deprived. Mechanistically, the absence of exogenous glutamine sufficiently reduces glutamate levels to convert dimeric GLS1 to a self-assembled, extremely low-Km filamentous polymer. GLS1 filaments possess an enhanced catalytic activity, which further depletes intracellular glutamine. Functionally, filamentous GLS1-dependent glutamine scarcity leads to inadequate synthesis of asparagine and mitogenome-encoded proteins, resulting in ROS-induced apoptosis that can be rescued by asparagine supplementation. Physiologically, we observed GLS1 filaments in solid tumors and validated the tumor-suppressive role of constitutively active, filamentous GLS1 mutants K320A and S482C in xenograft models. Our results change our understanding of GLS1 in cancer metabolism and suggest the therapeutic potential of promoting GLS1 filament formation.

Keywords:  apoptosis; glutaminase; glutamine metabolism

DOI:  https://doi.org/10.1016/j.molcel.2022.03.016
Expert Rev Mol Diagn. 2022 Apr 08.

Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer.

Gerardo M Nava, Luis Alberto Madrigal Perez.

   INTRODUCTION: Adaptations of eukaryotic cells to environmental changes are important for their survival. However, under some circumstances, microenvironmental changes promote that eukaryotic cells utilize a metabolic signature resembling a unicellular organism named the Warburg effect. Most cancer cells share the Warburg effect displaying lactic fermentation and high glucose uptake. The Warburg effect also induces a metabolic rewiring stimulating glutamine consumption and lipid synthesis, also considered cancer hallmarks. Amino acid metabolism alteration due to the Warburg effect increases plasma levels of proline and branched-chain amino acids in several cancer types. Proline and lipids are probably used as electron transfer molecules in carcinogenic cells. In addition, branched-chain amino acids fuel the Krebs cycle, protein synthesis, and signaling in cancer cells.
AREAS COVERED: This review covers how metabolomics studies describe changes in some metabolites and proteins associated with the Warburg effect and related metabolic pathways.
EXPERT OPINION: In this review, we analyze the metabolic signature of the Warburg effect and related phenotypes and propose some Warburg effect-related metabolites and proteins (lactate, glucose uptake, glucose transporters, glutamine, branched-chain amino acids, proline, and some lipogenic enzymes) as promising cancer biomarkers.

Keywords:  Biomarker; Warburg effect; cancer; diagnosis; metabolism; molecular prognosis

DOI:  https://doi.org/10.1080/14737159.2022.2065196
Semin Cancer Biol. 2022 Apr 04. pii: S1044-579X(22)00079-7. [Epub ahead of print]

Metabolic Reservoir Cycles in Cancer.

Cissy Zhang, Addison Quinones, Anne Le.

  Cancer cells possess various biological processes to ensure survival and proliferation even under unfavorable conditions such as hypoxia, nutrient deprivation, and oxidative stress. One of the defining hallmarks of cancer cells is their ability to reprogram their metabolism to suit their needs. Building on over a decade of research in the field of cancer metabolism, numerous unique metabolic capabilities are still being discovered in the present day. One recent discovery in the field of cancer metabolism that was hitherto unexpected is the ability of cancer cells to store vital metabolites in forms that can be readily converted to glucose and glutamine for later use. We called these forms "metabolic reservoirs." While many studies have been conducted on storage molecules such as glycogen, triglyceride, and phosphocreatine (PCr), few have explored the concept of "metabolic reservoirs" for cancer as a whole. In this review, we will provide an overview of this concept, the previously known reservoirs including glycogen, triglyceride, and PCr, and the new discoveries made including the newly discovered reservoirs such as N-acetyl-aspartyl-glutamate (NAAG), lactate, and γ- aminobutyric acid (GABA). We will also discuss whether disrupting these reservoir cycles may be a new avenue for cancer treatment.

Keywords:  Metabolic reservoir; N-acetyl-aspartyl-glutamate (NAAG); cancer metabolism; gamma aminobutyric acid (GABA); lactate

DOI:  https://doi.org/10.1016/j.semcancer.2022.03.023
Subcell Biochem. 2022 ;98 15-40

Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.

Guillem Lambies, Cosimo Commisso.

  Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.

Keywords:  Cancer malignancy; Cell metabolism; Macropinocytosis; Nutrient scarcity; Nutrient uptake; Stress stimuli

DOI:  https://doi.org/10.1007/978-3-030-94004-1_2
Adv Healthc Mater. 2022 Apr 08. e2102799

Metabolic Intervention Nanoparticles for triple-negative Breast Cancer Therapy Via Overcoming FSP1-mediated Ferroptosis Resistance.

Jie Yang, Zengguang Jia, Jun Zhang, Xiuhua Pan, Yawen Wei, Siyu Ma, Ning Yang, Zengyi Liu, Qi Shen.

  Triple-negative breast cancer (TNBC) patients have a predisposition to poor prognosis due to the strong malignancy. Ferroptosis, a new forms of cell death, is a candidate treatment for TNBC owing to its effectiveness in killing cancer cells. However, some TNBC cells exhibit an abnormal tumor metabolism, especially the ferroptosis suppressor protein 1 (FSP1)-mediated ubiquinone redox metabolism, which could promote ferroptosis resistance. Here, rosuvastatin (RSV) was encapsulated in silk fibroin (SF) nanoparticle (designated as Cu-SF(RSV) NPs) for TNBC inhibition by overcoming FSP1-mediated ferroptosis resistance. RSV intervened in metabolic mevalonate pathway to disturb the redox homeostasis regulated by CoQ/FSP1 axis, thereby overcoming ferroptosis resistance. Besides, Cu-SF(RSV) NPs could generate reactive oxygen species (ROS) and deplete glutathione (GSH) to facilitate redox stress, thereby amplifying ferroptosis effect. Thus, we anticipate that the metabolic intervention nanoparticles, Cu-SF(RSV) NPs, could be exploited as a promising therapeutic platform for clinical TNBC treatment. This article is protected by copyright. All rights reserved.

Keywords:  ferroptosis resistance; metabolic intervention; metastasis; statins-loaded silk fibroin nanoparticles; triple-negative breast cancer

DOI:  https://doi.org/10.1002/adhm.202102799
Pathol Oncol Res. 2022 ;28 1610231

In Situ Analysis of mTORC1/C2 and Metabolism-Related Proteins in Pediatric Osteosarcoma.

Anna Mohás, Ildikó Krencz, Zsófia Váradi, Gabriella Arató, Luca Felkai, Dorottya Judit Kiss, Dorottya Moldvai, Anna Sebestyén, Monika Csóka.

  Activation of the mTOR pathway has been observed in osteosarcoma, however the inhibition of mammalian target of rapamycin (mTOR) complex 1 has had limited results in osteosarcoma treatment. Certain metabolic pathways can be altered by mTOR activation, which can affect survival. Our aim was to characterize the mTOR profile and certain metabolic alterations in pediatric osteosarcoma to determine the interactions between the mTOR pathway and metabolic pathways. We performed immunohistochemistry on 28 samples to analyze the expression of mTOR complexes such as phospho-mTOR (pmTOR), phosphorylated ribosomal S6 (pS6), and rapamycin-insensitive companion of mTOR (rictor). To characterize metabolic pathway markers, we investigated the expression of phosphofructokinase (PFK), lactate dehydrogenase-A (LDHA), β-F1-ATPase (ATPB), glucose-6-phosphate dehydrogenase (G6PDH), glutaminase (GLS), fatty acid synthetase (FASN), and carnitin-O-palmitoyltransferase-1 (CPT1A). In total, 61% of the cases showed low mTOR activity, but higher pmTOR expression was associated with poor histological response to chemotherapy and osteoblastic subtype. Rictor expression was higher in metastatic disease and older age at the time of diagnosis. Our findings suggest the importance of the Warburg-effect, pentose-phosphate pathway, glutamine demand, and fatty-acid beta oxidation in osteosarcoma cells. mTOR activation is linked to several metabolic pathways. We suggest performing a detailed investigation of the mTOR profile before considering mTORC1 inhibitor therapy. Our findings highlight that targeting certain metabolic pathways could be an alternative therapeutic approach.

Keywords:  mTOR; metabolic; metabolic adaptation; osteosarcoma; pathways; pediatric

DOI:  https://doi.org/10.3389/pore.2022.1610231
OMICS. 2022 Apr 07.

Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.

Merve Kutay, Devrim Gozuacik, Tunahan Çakır.

  A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular. This work does not include any human subjects. We used data from literature, and they were cell-line data. Therefore, we do not have any IRB or Clinical Registration.

Keywords:  bioinformatics; cancer dormancy; cancer drug discovery; metabolic network models; preventive medicine; transcriptome

DOI:  https://doi.org/10.1089/omi.2022.0008
Front Oncol. 2022 ;12 857686

Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis.

Patries M Herst, Georgia M Carson, David A Eccles, Michael V Berridge.

  The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

Keywords:  bioenergetic flexibility; glycolysis-OXPHOS continuum; mito-nuclear gene expression; tumor microenvironment (TME); tumor progression and metastasis

DOI:  https://doi.org/10.3389/fonc.2022.857686
Mol Biol Rep. 2022 Apr 06.

Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study.

Marina A Bykanova, Maria A Solodilova, Iuliia E Azarova, Elena Y Klyosova, Olga Y Bushueva, Anna A Polonikova, Mikhail I Churnosov, Alexey V Polonikov.

   BACKGROUND: Glutathione is a tripeptide detoxifying a variety of exogenous and endogenous free radicals and carcinogens, and a deficiency of glutathione is associated with an increased host susceptibility to oxidative stress, a pathological condition implicated in the development and progression of cancer. The catalytic subunit of glutamate-cysteine ligase (GCLC) is an enzyme responsible for the initial and rate-limiting step of glutathione biosynthesis.
METHODS AND RESULTS: The aim of this pilot study was to investigate whether genetic variation at the GCLC gene contributes to the risk of colorectal cancer (CRC). DNA samples from 681 unrelated Russian individuals (283 patients with CRC and 398 age- and sex-matched healthy controls) were genotyped for six common functional SNPs of the GCLC gene (SNPs) such as rs12524494, rs17883901, rs606548, rs636933, rs648595 and rs761142 of the GCLC gene using the MassARRAY-4 system. We found that genotype rs606548-C/T is significantly associated with increased risk of CRC regardless of sex and age (OR 2.24; 95% CI 1.24-4.03; P = 0.007, FDR = 0.04). Moreover, ten GCLC genotype combinations showed association with the risk of CRC (P < 0.05). Functional SNP annotation enabled establishing the CRC-associated polymorphisms are associated with a decreased GCLC expression that may be attributed to epigenetic effects of histone modifications operating in a colon-specific manner.
CONCLUSIONS: The present study was the first to show that genetic variation at the catalytic subunit of glutamate-cysteine ligase may contribute to the risk of colorectal cancer risk. However, further genetic association studies with a larger sample size are required to substantiate the role of GCLC gene polymorphisms in the development of sporadic colorectal cancer.

Keywords:  Carcinogenesis; Colorectal cancer; Genetic predisposition to disease; Glutamate cysteine ligase; Glutathione; Single nucleotide polymorphism

DOI:  https://doi.org/10.1007/s11033-022-07406-0