bims-glucam 2023-02-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–02–26
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University

The mitochondrial chaperone TRAP-1 regulates the glutamine metabolism in tumor cells.
CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions.
Filament formation by glutaminase enzymes drives catalysis.
Methanodibenzo[b,f][1,5]dioxocins as Novel Glutaminase Inhibitor with Anti-Glioblastoma Potential.
Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells.
Nucleotide metabolism is linked to cysteine availability during ferroptosis.
HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.
Adrenocortical Carcinoma (ACC) Cells Rewire Their Metabolism to Overcome Curcumin Antitumoral Effects Opening a Window of Opportunity to Improve Treatment.
Metabolic programming and immune suppression in the tumor microenvironment.
ARPC1A correlates with poor prognosis in prostate cancer and is up-regulated by glutamine metabolism to promote tumor cell migration, invasion and cytoskeletal changes.
Unique Metabolic Contexts Sensitize Cancer Cells and Discriminate between Glycolytic Tumor Types.
Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells.
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer.
Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer.
Targeting immune-onco-metabolism for precision cancer therapy.
Metabolomics in oncology.
Cancer metabolism within tumor microenvironments.
Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.

Mitochondrion. 2023 Feb 22. pii: S1567-7249(23)00020-X. [Epub ahead of print]

The mitochondrial chaperone TRAP-1 regulates the glutamine metabolism in tumor cells.

Shrikant Purushottam Dharaskar, Amere Subbarao Sreedhar.

  Understanding cancer cell metabolism always provides information on hidden dimensions of tumor adaptations. Warburg's theory that cancer cells opt for aerobic glycolysis over the mitochondrial oxidative phosphorylation (OXPHOS) system is widely accepted. However, the hypothesis does not explain the mitochondrion's role in these cells. Here, we demonstrate that intact mitochondria are used for anaplerotic functions and ATP production by utilizing glutamine with the help of mitochondrial chaperone TRAP-1 (Tumor Necrosis Factor Receptor-associated Protein 1). TRAP-1 otherwise promotes aerobic glycolysis by lowering the mitochondrial OXPHOS in the presence of glucose. Here, we show that TRAP-1 maintains mitochondrial integrity and augments glutamine metabolism upon glucose deprivation to meet the cellular energy demand. The enhanced PER and ECAR correlating with increased ATP production suggest that glutamine fuels mitochondria in the presence of TRAP-1. We also found that TRAP1-dependent glutamine utilization involves the HIF2α-SLC1A5-GLS axis and is independent of hypoxia. Subsequently, we found that the metastatic potential of tumor cells is linked with glucose utilization, whereas the proliferative potential is linked with both glucose and glutamine utilization. Our findings establish that TRAP-1 contributes to enhanced glutamine utilization through the HIF2α-SLC1A5-GLS axis. Our results endow that TRAP-1 inhibitors can be potential drug candidates to combat tumor metabolism. Therefore, their use, either alone or in combination with existing chemotherapeutic agents, may target tumor metabolism and improve anticancer treatment response.

Keywords:  TRAP-1; cancer; glutamine; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.mito.2023.02.011
Nat Immunol. 2023 Feb 23.

CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions.

Pu-Ste Liu, Yi-Ting Chen, Xiaoyun Li, Pei-Chun Hsueh, Sheue-Fen Tzeng, Hsi Chen, Pei-Zhu Shi, Xin Xie, Sweta Parik, Mélanie Planque, Sarah-Maria Fendt, Ping-Chih Ho.

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD+/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.

DOI: https://doi.org/10.1038/s41590-023-01430-3
bioRxiv. 2023 Feb 16. pii: 2023.02.16.528860. [Epub ahead of print]

Filament formation by glutaminase enzymes drives catalysis.

Shi Feng, Cody Aplin, Thuy-Tien T Nguyen, Richard A Cerione.

The mitochondrial glutaminase enzymes initiate glutaminolysis by catalyzing the hydrolysis of glutamine to glutamate, satisfying the metabolic requirements of aggressive cancers and thus representing potential therapeutic targets. However, the mechanisms underlying their allosteric regulation are poorly understood. It has been suggested that glutaminases form oligomeric filament-like structures essential for their activation. Here, we provide structural evidence for the ability of the glutaminase enzymes to form filaments upon substrate binding, and present the first cryo-EM structures of the human full-length glutaminase isozyme GLS2 that offer an unprecedented view of the mechanism responsible for catalyzing glutamine hydrolysis. The GLS2 structures reveal that the 'activation loop', a motif previously identified to regulate enzymatic activity, assumes a unique conformation and works together with a 'lid' that closes over the active site to 'lock in' the substrate glutamine. Tyrosine 251 of the GLS2 activation loop forms a cation-π interaction with Lysine 222 in the active site, which in turn enables a key catalytic residue, Serine 219, to undergo deprotonation for nucleophilic attack on the substrate. These findings further suggest that allosteric glutaminase inhibitors disrupt this interaction, which is critical for catalysis, while activators stabilize it. The GLS2 structures also show how the ankyrin repeats regulate different glutaminase isozymes.

DOI: https://doi.org/10.1101/2023.02.16.528860
Cancers (Basel). 2023 Feb 05. pii: 1010. [Epub ahead of print]15(4):

Methanodibenzo[b,f][1,5]dioxocins as Novel Glutaminase Inhibitor with Anti-Glioblastoma Potential.

Akshaya Murugesan, Sana Kari, Anita Shrestha, Benedicta Assoah, Konda Mani Saravanan, Monica Murugesan, Ramesh Thiyagarajan, Nuno R Candeias, Meenakshisundaram Kandhavelu.

  Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2'-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between -10.2 and -9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski's rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.

Keywords:  characterization; glutaminase inhibitors; interaction; modeling; new dioxocin derivatives; signaling; synthesis

DOI:  https://doi.org/10.3390/cancers15041010
Biomolecules. 2023 Feb 10. pii: 345. [Epub ahead of print]13(2):

Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells.

Asitha Premaratne, Charles Ho, Shinjini Basu, Ashfia Fatima Khan, Tasneem Bawa-Khalfe, Chin-Yo Lin.

  Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and "degrader" activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics.

Keywords:  breast cancer; glutaminolysis; ligands; liver X receptor; metabolism

DOI:  https://doi.org/10.3390/biom13020345
J Biol Chem. 2023 Feb 17. pii: S0021-9258(23)00171-0. [Epub ahead of print] 103039

Nucleotide metabolism is linked to cysteine availability during ferroptosis.

Annamarie E Allen, Yudong Sun, Fangchao Wei, Michael A Reid, Jason W Locasale.

The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RSL3 or in-vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While inhibition of the glutathione peroxidase GPX4 caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RSL3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis, and points to nucleotide metabolism as an important target of cysteine deprivation.

DOI: https://doi.org/10.1016/j.jbc.2023.103039
EMBO J. 2023 Feb 20. e112067

HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.

Rindert Missiaen, Nicholas P Lesner, M Celeste Simon.

  A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.

Keywords:  HIF; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.15252/embj.2022112067
Cancers (Basel). 2023 Feb 07. pii: 1050. [Epub ahead of print]15(4):

Adrenocortical Carcinoma (ACC) Cells Rewire Their Metabolism to Overcome Curcumin Antitumoral Effects Opening a Window of Opportunity to Improve Treatment.

Marta Claudia Nocito, Paola Avena, Lucia Zavaglia, Arianna De Luca, Adele Chimento, Tarig Hamad, Davide La Padula, Davide Stancati, Constanze Hantel, Rosa Sirianni, Ivan Casaburi, Vincenzo Pezzi.

  Extensive research suggests that curcumin interferes with multiple cell signaling pathways involved in cancer development and progression. This study aimed to evaluate curcumin effects on adrenocortical carcinoma (ACC), a rare but very aggressive tumor. Curcumin reduced growth, migration and activated apoptosis in three different ACC cell lines, H295R, SW13, MUC-1. This event was related to a decrease in estrogen-related receptor-α (ERRα) expression and cholesterol synthesis. More importantly, curcumin changed ACC cell metabolism, increasing glycolytic gene expression. However, pyruvate from glycolysis was only minimally used for lactate production and the Krebs cycle (TCA). In fact, lactate dehydrogenase, extracellular acidification rate (ECAR), TCA genes and oxygen consumption rate (OCR) were reduced. We instead found an increase in Glutamic-Pyruvic Transaminase (GPT), glutamine antiport transporter SLC1A5 and glutaminase (GLS1), supporting a metabolic rewiring toward glutamine metabolism. Targeting this mechanism, curcumin effects were improved. In fact, in a low glutamine-containing medium, the growth inhibitory effects elicited by curcumin were observed at a concentration ineffective in default growth medium. Data from this study prove the efficacy of curcumin against ACC growth and progression and point to the concomitant use of inhibitors for glutamine metabolism to improve its effects.

Keywords:  ERRα; adrenocortical carcinoma; curcumin; glutamine; metabolism

DOI:  https://doi.org/10.3390/cancers15041050
Cancer Cell. 2023 Feb 09. pii: S1535-6108(23)00009-0. [Epub ahead of print]

Metabolic programming and immune suppression in the tumor microenvironment.

Emily N Arner, Jeffrey C Rathmell.

  Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies.

Keywords:  immune; metabolism; metastasis; plasticity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2023.01.009
Cell Biosci. 2023 Feb 22. 13(1): 38

ARPC1A correlates with poor prognosis in prostate cancer and is up-regulated by glutamine metabolism to promote tumor cell migration, invasion and cytoskeletal changes.

Ye-Hui Chen, Hang Chen, Ting-Ting Lin, Jun-Ming Zhu, Jia-Yin Chen, Ru-Nan Dong, Shao-Hao Chen, Fei Lin, Zhi-Bin Ke, Jin-Bei Huang, Yong Wei, Qing-Shui Zheng, Xue-Yi Xue, Ning Xu.

   OBJECTIVE: This study aimed to identify potential biomarkers for prostate cancer (PCa) progression and metastasis, and to discern their biological functions.
METHODS: Bioinformatics methods were used to screen for hub genes. The expression level of key hub genes in PCa was determined and their prognostic significance was examined. A series of functional assays were performed to investigate the function of the highest-ranking hub gene.
RESULTS: Actin related protein 2/3 complex subunit 1A (ARPC1A) was identified as the hub gene. ARPC1A was highly expressed in PCa tissues and cell lines, and was an independent prognostic factor for predicting biochemical recurrence after radical prostatectomy and overall survival of PCa patients. Knockdown of ARPC1A inhibited PCa cell migration, invasion and cytoskeleton formation, but had no impact on cell proliferation and cell cycle progression. In vivo, ARPC1A overexpression promoted lung metastasis of PCa, but had no efffect on tumor growth. Additionally, glutamine metabolism was identified as an upstream regulator of ARPC1A, and promoted migration, invasion and cytoskeletal changes of PCa cell through ARPC1A.
CONCLUSION: These findings suggested that ARPC1A, which correlates with poor prognosis in PCa, functions downstream of glutamine metabolism to regulate cytoskeletal changes, cellular migration and cellular invasion in this disease.

Keywords:  ARPC1A; Cytoskeleton formation; Glutamine metabolism; Prostate cancer

DOI:  https://doi.org/10.1186/s13578-023-00985-w
Cancers (Basel). 2023 Feb 11. pii: 1158. [Epub ahead of print]15(4):

Unique Metabolic Contexts Sensitize Cancer Cells and Discriminate between Glycolytic Tumor Types.

Jonathan A Chacon-Barahona, Jeffrey P MacKeigan, Nathan J Lanning.

  Cancer cells utilize variable metabolic programs in order to maintain homeostasis in response to environmental challenges. To interrogate cancer cell reliance on glycolytic programs under different nutrient availabilities, we analyzed a gene panel containing all glycolytic genes as well as pathways associated with glycolysis. Using this gene panel, we analyzed the impact of an siRNA library on cellular viability in cells containing only glucose or only pyruvate as the major bioenergetic nutrient source. From these panels, we aimed to identify genes that elicited conserved and glycolysis-dependent changes in cellular bioenergetics across glycolysis-promoting and OXPHOS-promoting conditions. To further characterize gene sets within this panel and identify similarities and differences amongst glycolytic tumor RNA-seq profiles across a pan-cancer cohort, we then used unsupervised statistical classification of RNA-seq profiles for glycolytic cancers and non-glycolytic cancer types. Here, Kidney renal clear cell carcinoma (KIRC); Head and Neck squamous cell carcinoma (HNSC); and Lung squamous cell carcinoma (LUSC) defined the glycolytic cancer group, while Prostate adenocarcinoma (PRAD), Thyroid carcinoma (THCA), and Thymoma (THYM) defined the non-glycolytic cancer group. These groups were defined based on glycolysis scoring from previous studies, where KIRC, HNSC, and LUSC had the highest glycolysis scores, meanwhile, PRAD, THCA, and THYM had the lowest. Collectively, these results aimed to identify multi-omic profiles across cancer types with demonstrated variably glycolytic rates. Our analyses provide further support for strategies aiming to classify tumors by metabolic phenotypes in order to therapeutically target tumor-specific vulnerabilities.

Keywords:  cancer metabolism; glycolysis; glycolytic tumors; mTOR signaling; oxidative phosphorylation; pentose phosphate pathway

DOI:  https://doi.org/10.3390/cancers15041158
Cancer Metab. 2023 Feb 20. 11(1): 4

Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells.

Mika B Jekabsons, Mollie Merrell, Anna G Skubiz, Noah Thornton, Sandra Milasta, Douglas Green, Taosheng Chen, Yan-Hong Wang, Bharathi Avula, Ikhlas A Khan, Yu-Dong Zhou.

Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translational modification, flux analysis is necessary to conclusively establish phenotypes. In this study, the metabolic phenotypes of breast cancer cell lines with low (T47D) or high (MDA-MB-231) metastatic potential, as well as lung (LM)- and bone (BoM)-homing lines derived from MDA-MB-231 cells, were assessed by 13C metabolite labeling from [1,2-13C] glucose or [5-13C] glutamine and the rates of nutrient and oxygen consumption and lactate production. MDA-MB-231 and T47D cells produced 55 and 63%, respectively, of ATP from oxidative phosphorylation, whereas LM and BoM cells were more glycolytic, deriving only 20-25% of their ATP from mitochondria. ATP demand by BoM and LM cells was approximately half the rate of the parent cells. Of the anabolic fluxes assessed, nucleotide synthesis was the major ATP consumer for all cell lines. Glycolytic NADH production by LM cells exceeded the rate at which it could be oxidized by mitochondria, suggesting that the malate-aspartate shuttle was not involved in re-oxidation of these reducing equivalents. Serine synthesis was undetectable in MDA-MB-231 cells, whereas 3-5% of glucose was shunted to serine by LM and BoM lines. Proliferation rates of T47D, BoM, and LM lines tightly correlated with their respiration-normalized NADPH production rates. In contrast, MDA-MB-231 cells produced NADPH and GSH at higher rates, suggesting this line is more oxidatively stressed. Approximately half to two-thirds of NADPH produced by T47D, MDA-MB-231, and BoM cells was from the oxidative PPP, whereas the majority in LM cells was from the folate cycle. All four cell lines used the non-oxidative PPP to produce pentose phosphates, although this was most prominent for LM cells. Taken together, the metabolic phenotypes of LM and BoM lines differed from the parent line and from each other, supporting the metabolic re-wiring hypothesis as a feature of metastasis to lung and bone.

DOI: https://doi.org/10.1186/s40170-023-00303-5
bioRxiv. 2023 Feb 18. pii: 2023.02.17.528937. [Epub ahead of print]

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R Flint, Claire M Connell, Michael Lukey, Eileen P White, Anthony P Coll, Ashok R Venkitaraman, Tobias Janowitz.

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

DOI: https://doi.org/10.1101/2023.02.17.528937
iScience. 2023 Feb 17. 26(2): 106020

Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer.

Deanna Glassman, Mark S Kim, Meredith Spradlin, Sunil Badal, Mana Taki, Pratip Bhattacharya, Prasanta Dutta, Charles V Kingsley, Katherine I Foster, Olamide Animasahun, Jin Heon Jeon, Abhinav Achreja, Anusha Jayaraman, Praveen Kumar, Minal Nenwani, Fulei Wuchu, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda Mangala, Sanghoon Lee, Timothy A Yap, Shannon N Westin, Livia S Eberlin, Deepak Nagrath, Anil K Sood.

  Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence of resistance to AVA therapy resulted in a decreased metabolic conversion of pyruvate to lactate as assessed by hyperpolarized magnetic resonance spectroscopy and demonstrated robust antitumor effects with a survival advantage. Given the increasing population of patients receiving AVA therapy, these findings justify further development of GLSi in AVA resistance.

Keywords:  Cancer; Cellular physiology; Oncology

DOI:  https://doi.org/10.1016/j.isci.2023.106020
Cancers (Basel). 2023 Feb 13. pii: 1192. [Epub ahead of print]15(4):

Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer.

Fabrizio Fontana, Martina Anselmi, Patrizia Limonta.

  Prostate cancer (PCa) is the second leading cause of cancer deaths among men in Western countries. Mitochondria, the "powerhouse" of cells, undergo distinctive metabolic and structural dynamics in different types of cancer. PCa cells experience peculiar metabolic changes during their progression from normal epithelial cells to early-stage and, progressively, to late-stage cancer cells. Specifically, healthy cells display a truncated tricarboxylic acid (TCA) cycle and inefficient oxidative phosphorylation (OXPHOS) due to the high accumulation of zinc that impairs the activity of m-aconitase, the enzyme of the TCA cycle responsible for the oxidation of citrate. During the early phase of cancer development, intracellular zinc levels decrease leading to the reactivation of m-aconitase, TCA cycle and OXPHOS. PCa cells change their metabolic features again when progressing to the late stage of cancer. In particular, the Warburg effect was consistently shown to be the main metabolic feature of late-stage PCa cells. However, accumulating evidence sustains that both the TCA cycle and the OXPHOS pathway are still present and active in these cells. The androgen receptor axis as well as mutations in mitochondrial genes involved in metabolic rewiring were shown to play a key role in PCa cell metabolic reprogramming. Mitochondrial structural dynamics, such as biogenesis, fusion/fission and mitophagy, were also observed in PCa cells. In this review, we focus on the mitochondrial metabolic and structural dynamics occurring in PCa during tumor development and progression; their role as effective molecular targets for novel therapeutic strategies in PCa patients is also discussed.

Keywords:  OXPHOS; Warburg effect; mitochondrial dynamics; mitochondrial metabolism; prostate cancer

DOI:  https://doi.org/10.3390/cancers15041192
Front Oncol. 2023 ;13 1124715

Targeting immune-onco-metabolism for precision cancer therapy.

Sakshi Pajai, Jyoti E John, Satyendra Chandra Tripathi.

  Immune cells play a key role in host defence against infection and cancer. Unlike infection, cancer is a multidimensional disease where cancer cells require continuous activation of certain pathways to sustain their growth and survival. The tumour milieu plays an important role in defining the metabolic reprogramming to support this growth and evasion from the immune system. Cancer and stromal cells modulate each other's metabolism during cancer progression or regression. The mechanism related to change in the metabolism and its role in the crosstalk between tumour and immune cells is still an area of immense importance. Current treatment modalities can be immensely complemented and benefited by targeting the immuno-oncology metabolism, that can improve patient prognosis. This emerging aspect of immune-oncology metabolism is reviewed here, discussing therapeutic possibilities within various metabolic pathways and their effect on immune and cancer cell metabolism.

Keywords:  cancer; immune cells; immuno-oncology; metabolic reprogramming; metabolism; therapeutics; tumour immunology

DOI:  https://doi.org/10.3389/fonc.2023.1124715
Cancer Rep (Hoboken). 2023 Feb 21. e1795

Metabolomics in oncology.

Gurparsad Singh Suri, Gurleen Kaur, Giuseppina M Carbone, Dheeraj Shinde.

   BACKGROUND: Oncogenic transformation alters intracellular metabolism and contributes to the growth of malignant cells. Metabolomics, or the study of small molecules, can reveal insight about cancer progression that other biomarker studies cannot. Number of metabolites involved in this process have been in spotlight for cancer detection, monitoring, and therapy.
RECENT FINDINGS: In this review, the "Metabolomics" is defined in terms of current technology having both clinical and translational applications. Researchers have shown metabolomics can be used to discern metabolic indicators non-invasively using different analytical methods like positron emission tomography, magnetic resonance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically feasible way to track changes in tumor metabolism and gauge treatment response across time. Recent studies have shown metabolomics can also predict individual metabolic changes in response to cancer treatment, measure medication efficacy, and monitor drug resistance. Its significance in cancer development and treatment is summarized in this review.
CONCLUSION: Although in infancy, metabolomics can be used to identify treatment options and/or predict responsiveness to cancer treatments. Technical challenges like database management, cost and methodical knowhow still persist. Overcoming these challenges in near further can help in designing new treatment régimes with increased sensitivity and specificity.

Keywords:  biomarker; cancer; metabolic reprogramming; metabolism; metabolomics

DOI:  https://doi.org/10.1002/cnr2.1795
Biochim Biophys Acta Gen Subj. 2023 Feb 16. pii: S0304-4165(23)00028-4. [Epub ahead of print]1867(5): 130330

Cancer metabolism within tumor microenvironments.

Sho Aki, Ryuichi Nakahara, Keisuke Maeda, Tsuyoshi Osawa.

   BACKGROUND: Tumor microenvironments could determine cancer heterogeneity and malignancy. Hypoxia, nutrition starvation, and acidic pH could contribute to cancer malignancy associated with genetic, epigenetic, and metabolic alterations, promoting invasion and metastasis. Cancer cells adapting to extreme tumor microenvironments could enable evasion of cell death and immune responses. It could stimulate drug resistance and recurrence, resulting in poor patient prognosis. Therefore, investigating druggable targets of the malignant cancer cells within tumor microenvironments is necessary, but such treatments are limited. Cell-cell metabolic interaction may also contribute to cancer malignancy within the tumor microenvironments. Organelle-organelle interactions have recently gained attention as new cancer therapy targets as they play essential roles in the metabolic adaptation to the tumor microenvironment. In this review, we overview (1) metabolic alterations within tumor microenvironments, (2) cell-to-cell, and (3) organelle-to-organelle metabolic interactions, and we add novel insights into cancer therapy.

Keywords:  Acidic pH; Cancer metabolism; Cell-cell interactions; Hypoxia; Nutrient starvation; Organelle

DOI:  https://doi.org/10.1016/j.bbagen.2023.130330
ASN Neuro. 2023 Jan-Dec;15:15 17590914231157974

Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.

Isadora Matias, Luan Pereira Diniz, Ana Paula Bergamo Araujo, Isabella Vivarini Damico, Pâmella de Moura, Felipe Cabral-Miranda, Fabiola Diniz, Belisa Parmeggiani, Valeria de Mello Coelho, Renata E P Leite, Claudia K Suemoto, Gustavo Costa Ferreira, Regina Célia Cussa Kubrusly, Flávia Carvalho Alcantara Gomes.

  Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes in vitro undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [3H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [3H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.

Keywords:  GLT-1; aging; astrocyte; glutamate-glutamine cycle; hippocampus; senescence

DOI:  https://doi.org/10.1177/17590914231157974