bims-glucam 2023-05-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–05–21
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer.
PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.
The Ubiquitin-Proteasome System in Tumor Metabolism.
Microfluidic Devices for Precise Measurements of Cell Directionality Reveal a Role for Glutamine during Cell Migration.
Impact of acute stress on murine metabolomics and metabolic flux.
Cystine/Glutamate Xc- Antiporter Induction Compensates for Transsulfuration Pathway Repression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) to Ensure Cysteine for Hepatic Glutathione Biosynthesis.
Alpha-ketoglutarate-dependent enzymes in breast cancer and therapeutic implications.
A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.
Redox perturbations in yeast cells lacking glutathione reductase.

bioRxiv. 2023 May 05. pii: 2023.05.05.539577. [Epub ahead of print]

Asparagine synthetase and G-protein coupled estrogen receptor are critical responders to nutrient supply in KRAS mutant colorectal cancer.

Lingeng Lu, Qian Zhang, Xinyi Shen, Pinyi Zhen, Audrey Marin, Rolando Garcia- Milian, Jatin Roper, Sajid A Khan, Caroline H Johnson.

The nutrient status of the tumor microenvironment has major impacts on cell growth. Under nutrient depletion, asparagine synthetase (ASNS)-mediated asparagine production increases to sustain cell survival. G protein-coupled estrogen receptor-1 (GPER1) signaling converges via cAMP/PI3K/AKT with KRAS signaling to regulate ASNS expression. However, the role of GPER1 in CRC progression is still debated, and the effect of nutrient supply on both ASNS and GPER1 relative to KRAS genotype is not well understood. Here, we modeled a restricted nutrient supply by eliminating glutamine from growing cancer cells in a 3D spheroid model of human female SW48 KRAS wild-type (WT) and KRAS G12A mutant (MT) CRC cells, to examine effects on ASNS and GPER1 expression. Glutamine depletion significantly inhibited cell growth in both KRAS MT and WT cells; however, ASNS and GPER1 were upregulated in KRAS MT compared to WT cells. When nutrient supply was adequate, ASNS and GPER1 were not altered between cell lines. The impact of estradiol, a ligand for GPER1, was examined for any additional effects on cell growth. Under glutamine deplete conditions, estradiol decreased the growth of KRAS WT cells but had no effect on KRAS MT cells; estradiol had no additive or diminutive effect on the upregulation of ASNS or GPER1 between the cell lines. We further examined the association of GPER1 and ASNS levels with overall survival in a clinical colon cancer cohort of The Cancer Genome Atlas. Both high GPER1 and ASNS expression associated with poorer overall survival for females only in advanced stage tumors. These findings suggest that KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. ASNS and GPER1 may therefore be potential therapeutic targets that can be exploited to manage and control KRAS MT CRC.

DOI: https://doi.org/10.1101/2023.05.05.539577
Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2217826120

PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.

Bo Kyung Yoon, Hyeonhui Kim, Tae Gyu Oh, Se Kyu Oh, Sugyeong Jo, Minki Kim, Kyu-Hye Chun, Nahee Hwang, Suji Lee, Suyon Jin, Annette R Atkins, Ruth T Yu, Michael Downes, Jae-Woo Kim, Hyunkyung Kim, Ronald M Evans, Jae-Ho Cheong, Sungsoon Fang.

  Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.

Keywords:  3 phosphoglycerate dehydrogenase; gastric cancer; glutaminase; metabolic plasticity

DOI:  https://doi.org/10.1073/pnas.2217826120
Cancers (Basel). 2023 Apr 20. pii: 2385. [Epub ahead of print]15(8):

The Ubiquitin-Proteasome System in Tumor Metabolism.

Jie Wang, Yuandi Xiang, Mengqi Fan, Shizhen Fang, Qingquan Hua.

  Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the "Warburg effect," play an essential part in tumor metabolic reprogramming. In addition, fatty acids are harnessed to satisfy the increased requirement for the phospholipid components of biological membranes and energy. Moreover, the anabolism/catabolism of amino acids, such as glutamine, cystine, and serine, provides nitrogen donors for biosynthesis processes, development of the tumor inflammatory environment, and signal transduction. The ubiquitin-proteasome system (UPS) has been widely reported to be involved in various cellular biological activities. A potential role of UPS in the metabolic regulation of tumor cells has also been reported, but the specific regulatory mechanism has not been elucidated. Here, we review the role of ubiquitination and deubiquitination modification on major metabolic enzymes and important signaling pathways in tumor metabolism to inspire new strategies for the clinical treatment of cancer.

Keywords:  metabolism; signaling pathway; treatment; tumor; ubiquitin–proteasome system modification

DOI:  https://doi.org/10.3390/cancers15082385
Res Sq. 2023 May 03. pii: rs.3.rs-2799430. [Epub ahead of print]

Microfluidic Devices for Precise Measurements of Cell Directionality Reveal a Role for Glutamine during Cell Migration.

Nil Gural, Daniel Irimia.

Cancer cells that migrate from tumors into surrounding tissues are responsible for cancer dissemination through the body. Microfluidic devices have been instrumental in discovering unexpected features of cancer cell migration, including the migration in self-generated gradients and the contributions of cell-cell contact during collective migration. Here, we design microfluidic channels with five successive bifurcations to characterize the directionality of cancer cell migration with high precision. We find that the directional decisions of cancer cells moving through bifurcating channels in response to self-generated epidermal growth factor (EGF) gradients require the presence of glutamine in the culture media. A biophysical model helps quantify the contribution of glucose and glutamine to cancer cell orientation during migration in self-generated gradients. Our study uncovers an unexpected interplay between cancer cell metabolism and cancer cell migration studies and may eventually lead to new ways to delay cancer cell invasion.

DOI: https://doi.org/10.21203/rs.3.rs-2799430/v1
Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301215120

Impact of acute stress on murine metabolomics and metabolic flux.

Won Dong Lee, Lingfan Liang, Jenna AbuSalim, Connor S R Jankowski, Laith Z Samarah, Michael D Neinast, Joshua D Rabinowitz.

  Plasma metabolite concentrations and labeling enrichments are common measures of organismal metabolism. In mice, blood is often collected by tail snip sampling. Here, we systematically examined the effect of such sampling, relative to gold-standard sampling from an in-dwelling arterial catheter, on plasma metabolomics and stable isotope tracing. We find marked differences between the arterial and tail circulating metabolome, which arise from two major factors: handling stress and sampling site, whose effects were deconvoluted by taking a second arterial sample immediately after tail snip. Pyruvate and lactate were the most stress-sensitive plasma metabolites, rising ~14 and ~5-fold. Both acute handling stress and adrenergic agonists induce extensive, immediate production of lactate, and modest production of many other circulating metabolites, and we provide a reference set of mouse circulatory turnover fluxes with noninvasive arterial sampling to avoid such artifacts. Even in the absence of stress, lactate remains the highest flux circulating metabolite on a molar basis, and most glucose flux into the TCA cycle in fasted mice flows through circulating lactate. Thus, lactate is both a central player in unstressed mammalian metabolism and strongly produced in response to acute stress.

Keywords:  catecholamine; in vivo; isotope tracing; metabolomics; stress

DOI:  https://doi.org/10.1073/pnas.2301215120
Chem Res Toxicol. 2023 May 15.

Cystine/Glutamate Xc- Antiporter Induction Compensates for Transsulfuration Pathway Repression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) to Ensure Cysteine for Hepatic Glutathione Biosynthesis.

Karina Orlowska, Russ R Fling, Rance Nault, Anthony L Schilmiller, Timothy R Zacharewski.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with the induction of oxidative stress and the progression of steatosis to steatohepatitis with fibrosis. It also disrupts metabolic pathways including one-carbon metabolism (OCM) and the transsulfuration pathway with possible consequences on glutathione (GSH) levels. In this study, complementary RNAseq and metabolomics data were integrated to examine the hepatic transsulfuration pathway and glutathione biosynthesis in mice following treatment with TCDD every 4 days for 28 days. TCDD dose-dependently repressed hepatic cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) mRNA and protein levels. Reduced CBS and CTH levels are also correlated with dose-dependent decreases in hepatic extract hydrogen sulfide (H2S). In contrast, cysteine levels increased consistent with the induction of Slc7a11, which encodes for the cystine/glutamate Xc- antiporter. Cotreatment of primary hepatocytes with sulfasalazine, a cystine/glutamate Xc- antiporter inhibitor, decreased labeled cysteine incorporation into GSH with a corresponding increase in TCDD cytotoxicity. Although reduced and oxidized GSH levels were unchanged following treatment due to the induction of GSH/GSSG efflux transporter by TCDD, the GSH:GSSG ratio decreased and global protein S-glutathionylation levels in liver extracts increased in response to oxidative stress along with the induction of glutamate-cysteine ligase catalytic subunit (Gclc), glutathione synthetase (Gss), glutathione disulfide reductase (Gsr), and glutathione transferase π (Gstp). Furthermore, levels of ophthalmic acid, a biomarker of oxidative stress indicating GSH consumption, were also increased. Collectively, the data suggest that increased cystine transport due to cystine/glutamate Xc- antiporter induction compensated for decreased cysteine production following repression of the transsulfuration pathway to support GSH synthesis in response to TCDD-induced oxidative stress.

DOI: https://doi.org/10.1021/acs.chemrestox.3c00017
Endocrinology. 2023 May 19. pii: bqad080. [Epub ahead of print]

Alpha-ketoglutarate-dependent enzymes in breast cancer and therapeutic implications.

Jingjing Xiong, Chaojun Yan, Qing Zhang, Jing Zhang.

  Alpha-ketoglutarate (α-KG)-dependent dioxygenases are a superfamily of enzymes that require oxygen, reduced iron and α-ketoglutarate for their catalytic functions. Therefore, they have the potential to sense the availabilities of oxygen, iron and specific metabolites, including α-KG and its structurally related metabolites. These enzymes play essential roles in various biological processes, including cellular adaptation to hypoxia, epigenetic and epitranscriptomic regulation of gene expression, and metabolic reprogramming. Many α-KG-dependent dioxygenases are dysregulated in cancer pathogenesis. Herein, we review how they are regulated and function in breast cancer, which may offer new therapeutic intervention strategies for targeting this family of enzymes.

Keywords:  breast cancer; demethylase; hydroxylase; hypoxia; therapeutic strategy; α-KG-dependent dioxygenases

DOI:  https://doi.org/10.1210/endocr/bqad080
Adv Healthc Mater. 2023 May 19. e2300220

A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.

Hongbo Gan, Xie Huang, Xi Luo, Jinlin Li, Banghui Mo, Lizhi Cheng, Qiuxia Shu, Zaizhi Du, Hong Tang, Wei Sun, Liting Wang, Shenglin Luo, Songtao Yu.

  Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effect. In this work, we present a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enables to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than Cyclophosphamide (CTX), a classic drug commonly recommended for TNBC patients in clinic. Hence, our reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment. This article is protected by copyright. All rights reserved.

Keywords:  ferroptosis; glutathione; heptamethine dye; mitochondria; theranostics

DOI:  https://doi.org/10.1002/adhm.202300220
Fungal Genet Biol. 2023 May 10. pii: S1087-1845(23)00041-5. [Epub ahead of print]167 103810

Redox perturbations in yeast cells lacking glutathione reductase.

Agnieszka Janeczko, Michał Przywara, Roman Maslanka, Barbara Raś, Klaudia Ziaja, Magdalena Kwolek-Mirek, Renata Zadrag-Tecza, Sabina Bednarska.

  Cellular redox homeostasis has a major effect on cell functions and its maintenance is supported by glutathione and protein thiols which serve as redox buffers in cells. The regulation of the glutathione biosynthetic pathway is a focus of a lot of scientific research. However, still little is known about how complex cellular networks influence glutathione homeostasis. In this work was used an experimental system based on an S. cerevisiae yeast mutant with a lack of the glutathione reductase enzyme and allyl alcohol as a precursor of acrolein inside the cell to determine the cellular processes influencing glutathione homeostasis. The absence of Glr1p slows down the growth rate of the cell population, especially in the presence of allyl alcohol, but does not lead to complete inhibition of the cell's reproductive capacity. It also amends the GSH/GSSG ratio and the share of NADPH and NADP+ in the total NADP(H) pool. The obtained results show that potential pathways involved in the maintenance of redox homeostasis are based from one side on de novo synthesis of GSH as indicated by increased activity of γ-GCS and increased expression of GSH1 gene in the Δglr1 mutant, from the other hand, on increased the level of NADPH. This is because the lower ratio of GSH/GSSG can be counterbalanced with the NADPH/NADP+ alternative system. The higher level of NADPH can be used by the thioredoxin system and other enzymes requiring NADPH to reduce cytosolic GSSG and maintain glutathione redox potential.

Keywords:  Acrolein; Glutathione; Glutathione reductase; NADPH; Redox state; Yeast

DOI:  https://doi.org/10.1016/j.fgb.2023.103810