bims-glucam 2023-11-19 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023‒11‒19
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
Fructose-1,6-bisphosphatase 1 suppresses PPARα-mediated gene transcription and non-small-cell lung cancer progression.
Identification of a prognostic evaluator from glutamine metabolic heterogeneity studies within and between tissues in hepatocellular carcinoma.
Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation.
M. mazei glutamine synthetase and glutamine synthetase-GlnK1 structures reveal enzyme regulation by oligomer modulation.
Mitochondrial adaptation decreases drug sensitivity of persistent triple negative breast cancer cells surviving combinatory and sequential chemotherapy.
Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Nat Metab. 2023 Nov 13.

Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.

Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky.

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.

DOI: https://doi.org/10.1038/s42255-023-00919-3
Am J Cancer Res. 2023 ;13(10): 4742-4754

Fructose-1,6-bisphosphatase 1 suppresses PPARα-mediated gene transcription and non-small-cell lung cancer progression.

Rongkai Shi, Jingjing Tao, Xiaoming Jiang, Min Li, Rongxuan Zhu, Shudi Luo, Zhimin Lu.

Rapidly growing tumors often encounter energy stress, such as glutamine deficiency. However, how normal and tumor cells differentially respond to glutamine deficiency remains largely unclear. Here, we demonstrate that glutamine deprivation activates PERK, which phosphorylates FBP1 at S170 and induces nuclear accumulation of FBP1. Nuclear FBP1 inhibits PPARα-mediated β-oxidation gene transcription in normal lung epithelial cells. In contrast, highly expressed OGT in non-small cell lung cancer (NSCLC) cells promotes FBP1 O-GlcNAcylation, which abrogates FBP1 phosphorylation and enhances β-oxidation gene transcription to support cell proliferation under glutamine deficiency. In addition, FBP1 pS170 is negatively correlated with OGT expression in human NSCLC specimens, and low expression of FBP1 pS170 is associated with poor prognosis in NSCLC patients. These findings highlight the differential regulation of FBP1 in normal and NSCLC cells under glutamine deprivation and underscore the potential to target nuclear FBP1 for NSCLC treatment.

Keywords: FBP1; O-GlcNAcylation; glutamine deprivation; non-small cell lung cancer (NSCLC); phosphorylation; prognostic biomarker
Front Pharmacol. 2023 ;14 1241677

Identification of a prognostic evaluator from glutamine metabolic heterogeneity studies within and between tissues in hepatocellular carcinoma.

Jie Bao, Yan Yu.

  Background: The liver is the major metabolic organ of the human body, and abnormal metabolism is the main factor influencing hepatocellular carcinoma (HCC). This study was designed to determine the effect of glutamine metabolism on HCC heterogeneity and to develop a prognostic evaluator based on the heterogeneity study of glutamine metabolism within HCC tumors and between tissues. Methods: Single-cell transcriptome data were extracted from the GSE149614 dataset and processed using the Seurat package in R for quality control of these data. HCC subtypes in the Cancer Genome Atlas and the GSE14520 dataset were identified via consensus clustering based on glutamine family amino acid metabolism (GFAAM) process genes. The machine learning algorithms gradient boosting machine, support vector machine, random forest, eXtreme gradient boosting, decision trees, and least absolute shrinkage and selection operator were utilized to develop the prognosis model of differentially expressed genes among the molecular gene subtypes. Results: The samples in the GSE149614 dataset included 10 cell types, and there was no significant difference in the GFAAM pathway. HCC was classified into three molecular subtypes according to GFAAM process genes, showing molecular heterogeneity in prognosis, clinicopathological features, and immune cell infiltration. C1 showed the worst survival rate and the highest immune score and immune cell infiltration. A six-gene model for prognostic and immunotherapy responses was constructed among subtypes, and the calculated high-risk score was significantly correlated with poor prognosis, high immune abundance, and a low response rate of immunotherapy in HCC. Conclusion: Our discovery of GFAAM-associated marker genes may help to further decipher the role in HCC occurrence and progression. In particular, this six-gene prognostic model may serve as a predictor of treatment and prognosis in HCC patients.

Keywords:  glutamine metabolism; hepatocellular carcinoma; immunotherapy; machine learning algorithm; prognosis; risk model; single-cell sequencing analysis

DOI:  https://doi.org/10.3389/fphar.2023.1241677
Nat Commun. 2023 Nov 16. 14(1): 7427

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.

Sadiya Parveen, Jessica Shen, Shichun Lun, Liang Zhao, Jesse Alt, Benjamin Koleske, Robert D Leone, Rana Rais, Jonathan D Powell, John R Murphy, Barbara S Slusher, William R Bishai.

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

DOI: https://doi.org/10.1038/s41467-023-43304-0
Int J Mol Sci. 2023 Oct 31. pii: 15787. [Epub ahead of print]24(21):

The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation.

Lilia Alberghina.

  The Warburg effect is the long-standing riddle of cancer biology. How does aerobic glycolysis, inefficient in producing ATP, confer a growth advantage to cancer cells? A new evaluation of a large set of literature findings covering the Warburg effect and its yeast counterpart, the Crabtree effect, led to an innovative working hypothesis presented here. It holds that enhanced glycolysis partially inactivates oxidative phosphorylation to induce functional rewiring of a set of TCA cycle enzymes to generate new non-canonical metabolic pathways that sustain faster growth rates. The hypothesis has been structured by constructing two metabolic maps, one for cancer metabolism and the other for the yeast Crabtree effect. New lines of investigation, suggested by these maps, are discussed as instrumental in leading toward a better understanding of cancer biology in order to allow the development of more efficient metabolism-targeted anticancer drugs.

Keywords:  ATP synthase; OXPHOS; ROS; cancer; cellular biochemistry; mitochondria

DOI:  https://doi.org/10.3390/ijms242115787
Nat Commun. 2023 Nov 15. 14(1): 7375

M. mazei glutamine synthetase and glutamine synthetase-GlnK1 structures reveal enzyme regulation by oligomer modulation.

Maria A Schumacher, Raul Salinas, Brady A Travis, Rajiv Ranjan Singh, Nicholas Lent.

Glutamine synthetases (GS) play central roles in cellular nitrogen assimilation. Although GS active-site formation requires the oligomerization of just two GS subunits, all GS form large, multi-oligomeric machines. Here we describe a structural dissection of the archaeal Methanosarcina mazei (Mm) GS and its regulation. We show that Mm GS forms unstable dodecamers. Strikingly, we show this Mm GS oligomerization property is leveraged for a unique mode of regulation whereby labile Mm GS hexamers are stabilized by binding the nitrogen regulatory protein, GlnK1. Our GS-GlnK1 structure shows that GlnK1 functions as molecular glue to affix GS hexamers together, stabilizing formation of GS active-sites. These data, therefore, reveal the structural basis for a unique form of enzyme regulation by oligomer modulation.

DOI: https://doi.org/10.1038/s41467-023-43243-w
Neoplasia. 2023 Nov 11. pii: S1476-5586(23)00073-8. [Epub ahead of print]46 100949

Mitochondrial adaptation decreases drug sensitivity of persistent triple negative breast cancer cells surviving combinatory and sequential chemotherapy.

Marie Winter, Amina Nait Eldjoudi, Catherine Guette, Hubert Hondermarck, Roland P Bourette, Quentin Fovez, William Laine, Bart Ghesquiere, Eric Adriaenssens, Jérôme Kluza, Xuefen Le Bourhis.

  Triple negative breast cancer (TNBC) is an aggressive malignancy for which chemotherapy remains the standard treatment. However, between 3 and 5 years after chemotherapy, about half patients will relapse and it is essential to identify vulnerabilities of cancer cells surviving neoadujuvant therapy. In this study, we established persistent TNBC cell models after treating MDA-MB-231 and SUM159-PT TNBC cell lines with epirubicin and cyclophosphamide, and then with paclitaxel, for a total of 18 weeks. The resulting chemo-persistent cell lines were more proliferative, both in vitro and in xenografted mice. Interestingly, MDA-MB-231 persistent cells became less sensitive to chemotherapeutic drugs, whereas SUM159-PT persistent cells kept similar sensitivity compared to control cells. The reduced sensitivity to chemotherapy in MDA-MB-231 persistent cells was found to be associated with an increased oxidative phosphorylation (OXPHOS) and modified levels of tricarboxylic acid cycle (TCA) intermediates. Integration of data from proteomics and metabolomics demonstrated TCA cycle among the most upregulated pathways in MDA-MB-231 persistent cells. The absence of glucose and pyruvate impeded OXPHOS in persistent cells, while the absence of glutamine did not. In contrast, OXPHOS was not modified in control cells independently of TCA substrates, indicating that MDA-MB-231 persistent cells evolved towards a more pyruvate dependent profile. Finally, the inhibition of pyruvate entry into mitochondria with UK-5099 reduced OXPHOS and re-sensitized persistent cells to therapeutic agents. Together, these findings suggest that targeting mitochondrial pyruvate metabolism may help to overcome mitochondrial adaptation of chemo-persistent TNBC.

Keywords:  Chemotherapy; Mitochondrial adaptation; Persistence; Pyruvate; Resistance

DOI:  https://doi.org/10.1016/j.neo.2023.100949
Transl Cancer Res. 2023 Oct 31. 12(10): 2911-2922

Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity.

Zi-Qian Wang, Ya-Qi Li, Dong-Yang Wang, Ying-Qiang Shen.

  Background: As a new form of cell death, ferroptosis has been shown to have inhibitory effects on a variety of tumor cells except oral squamous cell carcinoma (OSCC). There were few investigations on the effects and molecular mechanisms of piperlongumine (PL, a ferroptosis inducer) and CB-839 (a GLS1 inhibitor which promotes ferroptosis) on OSCC cells. This article assesses the anticancer effect and mechanism of PL as well as combined with CB-839.Methods: OSCC cells were treated with specified concentration of PL alone or with ferroptosis inhibitor Ferrostatin-1 (Fer-1) and antioxidant N-Acetylcysteine (NAC) to assess their effects on biological characteristics such as cell proliferation, cell death and intracellular ferroptosis related pathways. Also, cells were treated with PL combined with CB-839 to evaluate the synergistic effect of CB-839 on PL's anticancer effects.
Results: The results showed that the proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner. PL can induce OSCC cells apoptosis. Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment. We found some protein changes significantly such as the expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased. In addition, the anti-proliferation effect of PL can be reversed by Fer-1 and NAC and the level of LPO and ROS was decreased accordingly. Importantly, we found that PL and CB-839 in combination could decrease the cell viability and the LPO level synergistically, accompanied by a large consumption of glutathione (GSH). These evidences prove that PL can induce ferroptosis of OSCC cells, which can be enhanced by CB-839.
Conclusions: Our study suggested that the nature product PL can induce the ferroptotic death of OSCC cells, which is further enhanced when combined with CB-839. The synergistic anticancer effect of these two may prove new strategy for OSCC treatment.

Keywords:  CB-839; Piperlongumine (PL); ferroptosis; glutamine metabolism; peroxidation

DOI:  https://doi.org/10.21037/tcr-22-1494
bioRxiv. 2023 Oct 23. pii: 2023.10.20.563287. [Epub ahead of print]

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Mariko Takahashi, Harrison B Chong, Siwen Zhang, Matthew J Lazarov, Stefan Harry, Michelle Maynard, Ryan White, Heather E Murrey, Brendan Hilbert, Jason R Neil, Magdy Gohar, Maolin Ge, Junbing Zhang, Benedikt R Durr, Gregory Kryukov, Chih-Chiang Tsou, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Vilanueva, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, Jonathan Assaad, Farah Makram, Inbal Rachman, Neha Khandelwal, Pei-Chieh Tien, George Popoola, Nicholas Chen, Kira Vordermark, Marianne Richter, Himani Patel, Tzu-Yi Yang, Hanna Griesshaber, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lily Bussema, Rui Dong, Lei Shi, Martin Q Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, David E Fisher, Shyamala Maheswaran, Daniel A Haber, Genevieve Boland, Moshe Sade-Feldman, Russel Jenkins, Aaron Hata, Nabeel Bardeesy, Mario L Suva, Brent Martin, Brian Liau, Christopher Ott, Miguel N Rivera, Michael S Lawrence, Liron Bar-Peled.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

DOI: https://doi.org/10.1101/2023.10.20.563287