bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021‒04‒04
thirteen papers selected by
Sreeparna Banerjee
Middle East Technical University

  1. Pharmaceuticals (Basel). 2021 Mar 04. pii: 216. [Epub ahead of print]14(3):
      The glutaminolysis and serine-glycine-one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine-glycine-one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine-glycine-one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl- -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.
    Keywords:  SLC6A14 and SLC38A5; amino acid transporters; cancer-specific metabolism; glutamine addiction; oncometabolites; one-carbon metabolism
  2. Biomolecules. 2021 Mar 24. pii: 490. [Epub ahead of print]11(4):
      How cancer cells utilize nutrients to support their growth and proliferation in complex nutritional systems is still an open question. However, it is certainly determined by both genetics and an environmental-specific context. The interactions between them lead to profound metabolic specialization, such as consuming glucose and glutamine and producing lactate at prodigious rates. To investigate whether and how glucose and glutamine availability impact metabolic specialization, we integrated computational modeling on the genome-scale metabolic reconstruction with an experimental study on cell lines. We used the most comprehensive human metabolic network model to date, Recon3D, to build cell line-specific models. RNA-Seq data was used to specify the activity of genes in each cell line and the uptake rates were quantitatively constrained according to nutrient availability. To integrated both constraints we applied a novel method, named Gene Expression and Nutrients Simultaneous Integration (GENSI), that translates the relative importance of gene expression and nutrient availability data into the metabolic fluxes based on an observed experimental feature(s). We applied GENSI to study hepatocellular carcinoma addiction to glucose/glutamine. We were able to identify that proliferation, and lactate production is associated with the presence of glucose but does not necessarily increase with its concentration when the latter exceeds the physiological concentration. There was no such association with glutamine. We show that the integration of gene expression and nutrient availability data into genome-wide models improves the prediction of metabolic phenotypes.
    Keywords:  GENSI; Warburg effect; flux balance analysis; genome-scale metabolic map; glutamine addiction; hepatocellular carcinoma; metabolic network modeling
  3. FEBS J. 2021 Apr 03.
      Many metabolic phenotypes in cancer cells are also characteristic of proliferating non-transformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate, and provide a model to distinguish the metabolic influences of oncogenic mutations and non-oncogenic growth.
    Keywords:  Cancer metabolism; KRAS; branched-chain amino acids; cell growth; cell proliferation
  4. Phytother Res. 2021 Mar 31.
      Multidrug resistance (MDR) is one of the major obstacles for clinical effective chemotherapy. In this study, the effects and possible mechanisms of aloe-emodin (AE) were investigated on reversing the adriamycin (ADR)-induced resistance of MCF-7/ADR cells. AE could significantly reverse the ADR resistance in MCF-7/ADR cells. The combination of AE (20 μM) and ADR had no effect on the P-glycoprotein (P-gp) level, but notably promoted the accumulation of ADR in drug-resistant cells. The efflux function of P-gp required ATP, but AE reduced the intracellular ATP level. AE played a reversal role might through inhibiting the efflux function of P-gp. The research result of energy metabolism pathways indicated that combination of AE and ADR could inhibit glycolysis, tricarboxylic acid (TCA) cycle, glutamine metabolism, and related amino acid synthesis pathways. Moreover, we found AE not only reversed ADR-induced resistant but also induced autophagy as a defense mechanism. In addition, the combination of AE and ADR arrested G2/M cell cycle and induced apoptosis through DNA damage, ROS generation, caspase-3 activation. Our study indicated that AE could be a potential reversal agent to resensitize ADR resistant in tumor chemotherapy and inhibiting autophagy might be an effective strategy to further enhance the reversal activity of AE.
    Keywords:  P-glycoprotein (P-gp); adriamycin (ADR); aloe-emodin (AE); breast cancer; energy metabolism; multidrug resistance (MDR)
  5. Int J Mol Sci. 2021 Mar 24. pii: 3315. [Epub ahead of print]22(7):
      Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the "Warburg effect", the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions.
    Keywords:  P-glycoprotein; cancer cell metabolism; cancer stem cells; chemo-resistance; hepatocellular carcinoma; metabolic alteration; mitochondria
  6. RSC Adv. 2021 Feb 24. 11(13): 7115-7128
      In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical to cancer cells as it provides carbons for the TCA cycle to produce glutathione, fatty acids, and nucleotides, and contributes nitrogens to produce hexosamines, nucleotides, and many nonessential amino acids. Efforts to inhibit glutamine metabolism in cancer using amino acid analogs have been extensive. l-γ-Methyleneglutamine was shown to be of considerable biochemical importance, playing a major role in nitrogen transport in Arachis and Amorpha plants. Herein we report for the first time an efficient synthetic route to l-γ-methyleneglutamine and its amide derivatives. Many of these l-γ-methyleneglutamic acid amides were shown to be as efficacious as tamoxifen or olaparib at arresting cell growth among MCF-7 (ER+/PR+/HER2-), and SK-BR-3 (ER-/PR-/HER2+) breast cancer cells at 24 or 72 h of treatment. Several of these compounds exerted similar efficacy to olaparib at arresting cell growth among triple-negative MDA-MB-231 breast cancer cells by 72 h of treatment. None of the compounds inhibited cell growth in benign MCF-10A breast cells. Overall, N-phenyl amides and N-benzyl amides, such as 3, 5, 9, and 10, arrested the growth of all three (MCF-7, SK-BR-3, and MDA-MB-231) cell lines for 72 h and were devoid of cytotoxicity on MCF-10A control cells; N-benzyl amides with an electron withdrawing group at the para position, such as 5 and 6, inhibited the growth of triple-negative MDA-MB-231 cells commensurate to olaparib. These compounds hold promise as novel therapeutics for the treatment of multiple breast cancer subtypes.
  7. Evid Based Complement Alternat Med. 2021 ;2021 8832996
      Objective: This study aimed to find new biomarkers of prognosis and metabolomic therapy for gastric carcinoma (GC) treated with chemotherapy and investigate the metabolic mechanism of the Jianpi Yangzheng Xiaozheng (JPYZXZ) decoction in the treatment of GC.Methods: First, 36 patients with GC were randomly assigned to the treatment (chemotherapy plus JPYZXZ) and control (chemotherapy alone) groups. The clinical efficacy, side effects, and quality of life of patients in the two groups were evaluated after treatment. Then, the serum samples taken from 16 randomly selected patients (eight treatment cases and eight control cases with no evident pattern characters) and eight healthy volunteers were tested to identify the differential metabolite under the gas chromatography-time-of-fight mass spectrometry platform. The relevant metabolic pathways of differential substances were analyzed using multidimensional statistical analysis.
    Results: JPYZXZ combined with chemotherapy resulted in a lower risk of leucopenia, thrombocytopenia, and gastrointestinal reaction (P < 0.05). Additionally, patients in the treatment group showed a higher Karnofsky (KPS) scale (P < 0.05). Compared with healthy persons, patients with GC were found to have 26 significant differential metabolites after chemotherapy; these metabolites are mainly involved in 12 metabolic pathways, such as valine, leucine, and isoleucine biosynthesis. JPYZXZ primarily influences the pentose phosphate pathway; glutathione metabolism; glyoxylate and dicarboxylate metabolism; porphyrin and chlorophyll metabolism; and glycine, serine, and threonine metabolism of patients with GC treated with chemotherapy.
    Conclusions: The metabolic characteristics of patients with GC after chemotherapy are mainly various amino acid metabolic defects, especially L-glutamine, L-leucine, L-alloisoleucine, and L-valine. These defects lead to a series of problems, such as decreased tolerance and effectiveness of chemotherapy, increased side effects, decreased immunity, and shortened survival time. In addition, the remarkable upregulation of the gluconolactone level in patients with GC suggests the high proliferative activity of GC cells. Thus, gluconolactone may be used as a potential prognostic and diagnostic evaluation index. Moreover, JPYZXZ can reduce the incidence of ADRs and improve the life quality of patients by the correction of L-glutamine, L-leucine, L-alloisoleucine, and L-valine metabolism deficiency. In addition, gluconolactone metabolism is inhibited by JPYZXZ. Such inhibition may be one of the antitumor mechanisms of JPYZXZ.
  8. J Med Chem. 2021 Apr 01.
      The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.
  9. Molecules. 2021 Mar 25. pii: 1841. [Epub ahead of print]26(7):
      α-Ketoglutarate (AKG) is attracting much attention from researchers owing to its beneficial effects on anti-aging and cancer suppression, and, more recently, in nutritional supplements. Given that glucose is the main source of energy to maintain normal physiological functions of skeletal muscle, the effects of AKG supplementation for improving muscle performance are closely related to the glucose level in skeletal muscle. The differences of AKG-induced effects in skeletal muscle between two states of normal energy and energy deficiency are unclear. Furthermore, AKG-induced metabolic changes in skeletal muscles in different energy states also remain elusive. Here, we assessed the effects of AKG supplementation on mouse C2C12 myoblast cells cultured both in normal medium (Nor cells) and in low-glucose medium (Low cells), which were used to mimic two states of normal energy and energy deficiency, respectively. We further performed NMR-based metabolomic analysis to address AKG-induced metabolic changes in Nor and Low cells. AKG supplementation significantly promoted the proliferation and differentiation of cells in the two energy states through glutamine metabolism, oxidative stress, and energy metabolism. Under normal culture conditions, AKG up-regulated the intracellular glutamine level, changed the cellular energy status, and maintained the antioxidant capacity of cells. Under low-glucose culture condition, AKG served as a metabolic substrate to reduce the glutamine-dependence of cells, remarkably enhanced the antioxidant capacity of cells and significantly elevated the intracellular ATP level, thereby ensuring the normal growth and metabolism of cells in the state of energy deficiency. Our results provide a mechanistic understanding of the effects of AKG supplements on myoblasts in both normal energy and energy deficiency states. This work may be beneficial to the exploitation of AKG applications in clinical treatments and nutritional supplementations.
    Keywords:  AKG supplementation; biomolecular NMR; metabolic profile; metabolomics; myoblasts
  10. Neoplasia. 2021 Mar 27. pii: S1476-5586(21)00009-9. [Epub ahead of print]23(4): 391-399
      Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit glucose utilization for cancer treatment have not been successful. Recent evidence suggests that in addition to classical glucose transporters, sodium-glucose transporters (SGLTs) are expressed by cancers. We therefore investigated the possibility that SGLT inhibitors, which are used in treatment of type 2 diabetes, may exert antineoplastic activity by limiting glucose uptake. We show that the SGLT2 inhibitor canagliflozin inhibits proliferation of breast cancer cells. Surprisingly, the antiproliferative effects of canagliflozin are not affected by glucose availability nor by the level of expression of SGLT2. Canagliflozin reduces oxygen consumption and glutamine metabolism through the citric acid cycle. The antiproliferative effects of canagliflozin are linked to inhibition of glutamine metabolism that fuels respiration, which represents a previously unanticipated mechanism of its potential antineoplastic action.
    Keywords:  Breast cancer; Canagliflozin; Dapagliflozin; Glutamine; Tumor metabolism
  11. Toxicol Lett. 2021 Mar 26. pii: S0378-4274(21)00085-0. [Epub ahead of print]
      Arsenic is an environmental contaminant, which is widely distributed in soil, air, and water. There is sufficient evidence to indicate that arsenic increases the risk of bladder cancer in humans. However, its underlying mechanisms remain elusive. Glutamine (Gln) has multiple functions that promote carcinogenesis. Indeed, Gln transporters on cancer cells surface are often upregulated. Elevated expression levels of Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) have been reported in many types of human tumors. This study characterized the role of SLC1A5 in cell proliferation in arsenite-treated cells. In short-term experiments, SV-40 immortalized human uroepithelial (SV-HUC-1) cells were treated with Sodium arsenite (NaAsO2) (0, 0.5, 1, 2, 4, 8 μM) for 24 h. In long-term experiments, SV-HUC-1 cells were exposed to 0.5 μM NaAsO2 for 40 weeks. In both short-term and long-term experiments, arsenite increased expression of SLC1A5 by 1.89-fold and 2.25-fold, respectively. Arsenite increased Gln consumption of SV-HUC-1 cells, and Gln starvation inhibited cell proliferation in long-term arsenite-treated cells. Importantly, inhibiting SLC1A5 blocked cell proliferation by downregulating mTORC1 in long-term arsenite-treated cells. Moreover, SLC1A5 regulates mTORC1 in an αKG-dependent manner. Our results suggest that SLC1A5 plays an important role in cell proliferation of arsenite-treated SV-HUC-1 cells.
    Keywords:  Arsenic; Bladder cancer; Glutamine; SLC1A5; mTORC1
  12. Mol Ther. 2021 Mar 25. pii: S1525-0016(21)00146-5. [Epub ahead of print]
      Compared to normal cells, cancer cells exhibit specific metabolic characteristics that facilitate the growth and metastasis of cancer. It is now widely appreciated that long noncoding RNAs (lncRNAs) exert extensive regulatory effects on a spectrum of biological processes through diverse mechanisms. In this review, we focus on the rapidly advancing field of lncRNAs and summarize the relationship between the dysregulation of lncRNAs and cancer metabolism, with a particular emphasis on the specific roles of lncRNAs in glycolysis, mitochondrial function, glutamine and lipid metabolism. These investigations reveal that lncRNAs are a key factor in the complexity of malignant cancer metabolism. Only through understanding the relevance between lncRNAs and cancer metabolic reprogramming can we open a new chapter in the history of carcinogenesis, one that promises to alter the methods of cancer diagnosis and treatment.
    Keywords:  Cancer metabolism; LncRNA; Regulatory mechanism; Reprogramming
  13. Trends Endocrinol Metab. 2021 Mar 29. pii: S1043-2760(21)00049-7. [Epub ahead of print]
      Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.
    Keywords:  amino acid depletion therapy; amino acid metabolism; cancer; tumor metabolism