bims-glucam 2023-10-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–10–08
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Perfluorooctanoic acid-induced metabolic disorder via enhancing metabolism of glutamine and fatty acids in human intestinal cells.
Effect of MTA3 Inhibition of Glutamine Synthetase-Mediated Glutaminolysis on Radiosensitivity of Patients with Esophageal Cancer.
GLUL gene knockdown and restricted glucose level show synergistic inhibitory effect on the luminal subtype breast cancer MCF7 cells' proliferation and metastasis.
Comprehensive quantification of metabolic flux during acute cold stress in mice.
Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations.
Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer.
The aging tumor metabolic microenvironment.
Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy.
Targeted quantitative metabolic profiling of brain-derived cell cultures by semi-automated MEPS and LC-MS/MS.
The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.
Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3 is mediated by apoptotic cell death, NFκB activation, increased oxidative stress, and lower reduced glutathione status.
Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer.
Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.
Cystine/Glutamate antiporter system xc- deficiency impairs macrophage glutathione metabolism and cytokine production.

Environ Pollut. 2023 Oct 04. pii: S0269-7491(23)01686-X. [Epub ahead of print] 122684

Perfluorooctanoic acid-induced metabolic disorder via enhancing metabolism of glutamine and fatty acids in human intestinal cells.

Ruijia Zhang, Wenhua Lu, Lanyin Tu, Yingshi Lin, Jin Sun, Baowei Chen, Tiangang Luan.

  Intestinal cell metabolism plays an important role in intestine health. Perfluorooctanoic acid (PFOA) exposure could disorder intestinal cell metabolism. However, the mechanisms regarding how the three carbon sources interact under PFOA stress remined to be understood. The present study aimed to dissect the interconnections of glucose, glutamine, and fatty acids in PFOA-treated human colorectal cancer (DLD-1) cells using 13C metabolic flux analysis. The abundance of glycolysis and tricarboxylic acid (TCA) cycle metabolites was decreased in PFOA-treated cells except for succinate, whereas most of amino acids were more abundant. Beside serine and glycine, metabolites derived from 13C glucose was reduced in PFOA-treated cells, and the pentose phosphate pathway flux was 1.4-fold higher in PFOA-treated cells than in the controls. In reductive glutamine pathway, higher labeled enrichment of citrate, malate, fumarate, and succinate was observed for PFOA-treated cells. The contribution of glucose to fatty acid synthesis in PFOA-treated cells decreased while the contribution of glutamine to fatty acid synthesis increased. Additionally, synthesis of TCA intermediates from fatty acid β-oxidation was promoted in PFOA-treated cells. All results suggested that metabolic remodeling could happen in intestinal cells exposed to PFOA, which was potentially related to PFOA toxicity relevant with the loss of glucose in biomass synthesis and energy metabolism.

Keywords:  Glucose metabolism; Glutamine metabolism; Intestine health; Metabolic flux analysis; Metabolic remodeling; Perfluorooctanoic acid

DOI:  https://doi.org/10.1016/j.envpol.2023.122684
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)05572-4. [Epub ahead of print]117(2S): e227-e228

Effect of MTA3 Inhibition of Glutamine Synthetase-Mediated Glutaminolysis on Radiosensitivity of Patients with Esophageal Cancer.

L Du, Q Lei, Q Zhou, Y Du, X Lin, J Guo, C Li, Q Luo, C Fan, Q Guo.

PURPOSE/OBJECTIVE(S): Metastasis-associated protein 3 (MTA3) can serve as a tumor suppressor in many cancer types. However, the role of MTA3 in radiosensitivity of patients with esophageal squamous cell cancer (ESCC) remains unclear. We thus investigated the function of MTA3 in radiosensitivity for ESCC, one of the most common digestive cancers.
MATERIALS/METHODS: The colony formation assay and nude mice xenograft tumor assay were performed to investigate the effect of MTA3 on radiosensitivity in ESCC. Glutamine consumption assay kit and glutamate production assay kit were used to assess the glutaminolysis. Glutaminase (GLS) Activity Assay Kit and Glutamine Synthetase (GS) Activity Assay Kit were used to analyze the activity of specific metabolic enzymes dominate glutaminolysis. The regulatory mechanism of glutaminolysis by MTA3 was confirmed using Chromatin immunoprecipitation assay and Gaussia luciferase assay. The expression levels of MTA3 and GS in ESCC primary tissues were evaluated using immunohistochemistry. Survival curves were plotted with the Kaplan-Meier method and compared by log-rank test.
RESULTS: The colony formation assay showed that MTA3 depletion and overexpression caused significantly higher and lower clonogenic survival after different doses of irradiation (IR), respectively. When these cells were subcutaneously injected into nude mice, the tumors derived from the cells with MTA3 overexpression and MTA3 knockdown were significantly smaller and bigger after IR, respectively. These findings suggest that MTA3 can enhance radiosensitivity in vitro and in vivo. Meanwhile, overexpressed and knockdown MTA3 can repress and expedite glutamine consumption and glutamate production uniformly, respectively. To determine how MTA3 acts on glutaminolysis, the activity of two specific metabolic enzymes dominate this metabolism, GS and GLS, were evaluated. It found that overexpressed and knockdown MTA3 can restrain and enhance the activity of GS, respectively, but have less effect on GLS. Moreover, the decreased radiosensitivity mediated by MTA3 knockdown is significantly increased when treated with GS inhibitor, suggesting that GS plays a crucial role in MTA3-mediated radiosensitivity enhancement. Mechanistically, Chromatin immunoprecipitation assay and Gaussia luciferase assay showed that MTA3 was recruited to the promoter of GS and suppressed GS transcription. However, knockdown of GATA3 abolished MTA3's repressive effect on GS and inhibited the MTA3's occupation on the promoter region of GS. These results collectively demonstrated that, in ESCC cells, MTA3 is recruited by GATA3 to inhibit GS expression, then ultimately represses glutaminolysis and enhances radiosensitivity. Finally, we showed that the ESCC patients in the MTA3low/GShigh group is significantly associated with shorter overall survival.
CONCLUSION: MTA3 is capable of enhancing radiosensitivity through downregulating GS and MTA3low/GShigh might be a potential prognostic factor for ESCC patients.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.1138
EXCLI J. 2023 ;22 847-861

GLUL gene knockdown and restricted glucose level show synergistic inhibitory effect on the luminal subtype breast cancer MCF7 cells' proliferation and metastasis.

Arezu Karimpur Zahmatkesh, Mohammad Khalaj-Kondori, Mohammad Ali Hosseinpour Feizi, Behzad Baradaran.

  The glutamine synthetase path is one of the most important metabolic pathways in luminal breast cancer cells, which plays a critical role in supplying glutamine as an intermediate in the biosynthesis of amino acids and nucleotides. On the other hand, glycolysis and its dominant substrate, glucose, are the most critical players in cancer metabolism. Accordingly, targeting these two critical paths might be more efficient in luminal-type breast cancer treatment. MCF7 cells were cultivated in media containing 4.5, 2, and 1 g/L glucose to study its effects on GLUL (Glutamate Ammonia Ligase) expression. Followingly, high and low glucose cell cultures were transfected with 220 pM of siGLUL and incubated for 48 h at 37 ºC. The cell cycle progression and apoptosis were monitored and assessed by flow cytometry. Expression of GLUL, known as glutamine synthetase, was evaluated in mRNA and protein levels by qRT-PCR and western blotting, respectively. To examine the migration and invasion capacity of studied cells exploited from wound healing assay and subsequent expression studies of glutathione-S-transferase Mu3 (GSTM3) and alfa-enolase (ENO1). Expression of GLUL significantly decreased in cells cultured at lower glucose levels compared to those at higher glucose levels. siRNA-mediated knockdown of GLUL expression in low glucose cultures significantly reduced growth, proliferation, migration, and invasion of the MCF7 cells and enhanced their apoptosis compared to the controls. Based on the results, GLUL suppression down-regulated GSTM3, a main detoxifying enzyme, and up-regulated Bax. According to the role of glycolysis as a ROS suppressor, decreased amounts of glucose could be associated with increased ROS; it can be considered an efficient involved mechanism in this study. Also, increased expression of Bax could be attributable to mTOR/AKT inhibition following GLUL repression. In conclusion, utilizing GLUL and glycolysis inhibitors might be a more effective strategy in luminal-type breast cancer therapy. See also Figure 1(Fig. 1).

Keywords:  MCF7 cell line; cancer metabolism; glutamine synthetase; glycolysis; luminal breast cancer

DOI:  https://doi.org/10.17179/excli2023-6287
Cell Metab. 2023 Sep 27. pii: S1550-4131(23)00337-6. [Epub ahead of print]

Comprehensive quantification of metabolic flux during acute cold stress in mice.

Marc R Bornstein, Michael D Neinast, Xianfeng Zeng, Qingwei Chu, Jessie Axsom, Chelsea Thorsheim, Kristina Li, Megan C Blair, Joshua D Rabinowitz, Zoltan Arany.

  Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.

Keywords:  FBP1; brown adipose tissue; cold exposure; flux; gluconeogenesis; glucose; metabolomics; pyruvate carboxylase; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2023.09.002
Front Cell Dev Biol. 2023 ;11 1254313

Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations.

Katherine E Pendleton, Karen Wang, Gloria V Echeverria.

  Deregulation of tumor cell metabolism is widely recognized as a "hallmark of cancer." Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging "hallmark of cancer." Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients.

Keywords:  cancer; metabolism; oxphos (oxidative phosphorylation); plasticity; resistance

DOI:  https://doi.org/10.3389/fcell.2023.1254313
Sci Rep. 2023 Oct 06. 13(1): 16863

Amino acid transporter SLC38A5 is a tumor promoter and a novel therapeutic target for pancreatic cancer.

Tyler Sniegowski, Devaraja Rajasekaran, Souad R Sennoune, Sukumaran Sunitha, Fang Chen, Mohamed Fokar, Sudhir Kshirsagar, P Hemachandra Reddy, Ksenija Korac, Mosharaf Mahmud Syed, Tanima Sharker, Vadivel Ganapathy, Yangzom D Bhutia.

Pancreatic ductal adenocarcinoma (PDAC) cells have a great demand for nutrients in the form of sugars, amino acids, and lipids. Particularly, amino acids are critical for cancer growth and, as intermediates, connect glucose, lipid and nucleotide metabolism. PDAC cells meet these requirements by upregulating selective amino acid transporters. Here we show that SLC38A5 (SN2/SNAT5), a neutral amino acid transporter is highly upregulated and functional in PDAC cells. Using CRISPR/Cas9-mediated knockout of SLC38A5, we show its tumor promoting role in an in vitro cell line model as well as in a subcutaneous xenograft mouse model. Using metabolomics and RNA sequencing, we show significant reduction in many amino acid substrates of SLC38A5 as well as OXPHOS inactivation in response to SLC38A5 deletion. Experimental validation demonstrates inhibition of mTORC1, glycolysis and mitochondrial respiration in KO cells, suggesting a serious metabolic crisis associated with SLC38A5 deletion. Since many SLC38A5 substrates are activators of mTORC1 as well as TCA cycle intermediates/precursors, we speculate amino acid insufficiency as a possible link between SLC38A5 deletion and inactivation of mTORC1, glycolysis and mitochondrial respiration, and the underlying mechanism for PDAC attenuation. Overall, we show that SLC38A5 promotes PDAC, thereby identifying a novel, hitherto unknown, therapeutic target for PDAC.

DOI: https://doi.org/10.1038/s41598-023-43983-1
Curr Opin Biotechnol. 2023 Sep 30. pii: S0958-1669(23)00105-2. [Epub ahead of print]84 102995

The aging tumor metabolic microenvironment.

Steven E Pilley, Edgar Esparza, Peter J Mullen.

Despite the higher incidence of cancer with increasing age, few preclinical or clinical studies incorporate age. This, coupled with an aging world population, requires that we improve our understanding of how aging affects cancer development, progression, and treatment. One key area will be how the tumor microenvironment (TME) changes with age. Metabolite levels are an essential component of the TME, and they are affected by the metabolic requirements of the cells present and systemic metabolite availability. These factors are affected by aging, causing different TME metabolic states between young and older adults. In this review, we will summarize what is known about how aging impacts the TME metabolic state, and suggest how we can improve our understanding of it.

DOI: https://doi.org/10.1016/j.copbio.2023.102995
Front Oncol. 2023 ;13 1289397

Editorial: Cancer metabolism: molecular insights, metabolic crosstalk in the tumor microenvironment, and implications for therapy.

Balkrishna Chaube, Parmanand Malvi.



Keywords:  bioenergetics; cancer; cancer/immune metabolism; metabolic disorder and cancer; metabolic imaging; metabolomics; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1289397
J Pharm Biomed Anal. 2023 Sep 29. pii: S0731-7085(23)00526-5. [Epub ahead of print]236 115757

Targeted quantitative metabolic profiling of brain-derived cell cultures by semi-automated MEPS and LC-MS/MS.

Michele Protti, Marco Cirrincione, Sarah Palano, Eleonora Poeta, Giorgia Babini, Maria Chiara Magnifico, Simona Nicole Barile, Nicola Balboni, Francesca Massenzio, Mohammadreza Mahdavijalal, Federico M Giorgi, Roberto Mandrioli, Francesco M Lasorsa, Barbara Monti, Laura Mercolini.

  The accurate characterisation of metabolic profiles is an important prerequisite to determine the rate and the efficiency of the metabolic pathways taking place in the cells. Changes in the balance of metabolites involved in vital processes such as glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), as well as in the biochemical pathways related to amino acids, lipids, nucleotides, and their precursors reflect the physiological condition of the cells and may contribute to the development of various human diseases. The feasible and reliable measurement of a wide array of metabolites and biomarkers possesses great potential to elucidate physiological and pathological mechanisms, aid preclinical drug development and highlight potential therapeutic targets. An effective, straightforward, sensitive, and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach was developed for the simultaneous quali-quantitative analysis of 41 compounds in both cell pellet and cell growth medium obtained from brain-derived cell cultures. Sample pretreatment miniaturisation was achieved thanks to the development and optimisation of an original extraction/purification approach based on digitally programmed microextraction by packed sorbent (eVol®-MEPS). MEPS allows satisfactory and reproducible clean-up and preconcentration of both low-volume homogenate cell pellet lysate and cell growth medium with advantages including, but not limited to, minimal sample handling and method sustainability in terms of sample, solvents, and energy consumption. The MEPS-LC-MS/MS method showed good sensitivity, selectivity, linearity, and precision. As a proof of concept, the developed method was successfully applied to the analysis of both cell pellet and cell growth medium obtained from a line of mouse immortalised oligodendrocyte precursor cells (OPCs; Oli-neu cell line), leading to the unambiguous determination of all the considered target analytes. This method is thus expected to be suitable for targeted, quantitative metabolic profiling in most brain cell models, thus allowing accurate investigations on the biochemical pathways that can be altered in central nervous system (CNS) neuropathologies, including e.g., mitochondrial respiration and glycolysis, or use of specific nutrients for growth and proliferation, or lipid, amino acid and nucleotide metabolism.

Keywords:  Biomarkers; Brain cell cultures; Cell metabolism; LC-MS/MS; Targeted metabolic profiling

DOI:  https://doi.org/10.1016/j.jpba.2023.115757
Int J Biol Sci. 2023 ;19(15): 4915-4930

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Yuxin Liang, Jun He, Xiguang Chen, Liyang Yin, Qiong Yuan, Qiting Zeng, Xuyu Zu, Yingying Shen.

  Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

Keywords:  breast cancer; crosstalk; metabolism; targeted therapy; tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.86039
PLoS One. 2023 ;18(10): e0286758

Anti-proliferative effect of Cannabidiol in Prostate cancer cell PC3 is mediated by apoptotic cell death, NFκB activation, increased oxidative stress, and lower reduced glutathione status.

Jie Li, Tengfei Gu, Shengping Hu, Baiye Jin.

Prostate cancer is the second most frequent cancer diagnosed in men in the world today. Almost all prostate cancers are adenocarcinomas and develop from gland cells. We used the PC3 prostate cancer cell line, which is well studied and derived from a bone metastasis of a grade IV prostatic adenocarcinoma. Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, is a cannabinoid with anti-tumor properties but its effects on prostate cancer cells are not studied in detail. Here, we found cannabidiol decreased prostate cancer cell (PC3) viability up to 37.25% and induced apoptotic cell death in a time and dose-dependent manner. We found that CBD activated the caspases 3/7 pathways and increased DNA fragmentation. Furthermore, we observed an increase of pro-apoptotic genes Bax, an increased level of reactive oxygen species, lower reduced glutathione level, and altered mitochondrial potential in response to CBD treatment leading to lower cellular ATP. Overall, our results suggest that CBD may be effective against prostate cancer cells.

DOI: https://doi.org/10.1371/journal.pone.0286758
Cell Rep Med. 2023 Sep 27. pii: S2666-3791(23)00398-1. [Epub ahead of print] 101224

Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer.

YongHwan Kim, Hyein Ju, Seung-Yeon Yoo, Jinahn Jeong, Jinbeom Heo, Seungun Lee, Ja-Min Park, Sun Young Yoon, Se Un Jeong, Jinyoung Lee, HongDuck Yun, Chae-Min Ryu, Jinah Lee, Yun Ji Nam, Hyungu Kwon, Jaekyoung Son, Gowun Jeong, Ji-Hye Oh, Chang Ohk Sung, Eui Man Jeong, Jaehoon An, Sungho Won, Bumsik Hong, Jae Lyun Lee, Yong Mee Cho, Dong-Myung Shin.

  Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is the standard care for muscle-invasive bladder cancers (MIBCs). However, the complete response rate to this modality remains relatively low, and current clinicopathologic and molecular classifications are inadequate to predict NAC response in patients with MIBC. Here, we demonstrate that dysregulation of the glutathione (GSH) pathway is fundamental for MIBC NAC resistance. Comprehensive analysis of the multicohort transcriptomes reveals that GSH metabolism and immune-response genes are enriched in NAC-resistant and NAC-sensitive MIBCs, respectively. A machine-learning-based tumor/stroma classifier is applied for high-throughput digitalized immunohistochemistry analysis, finding that GSH dynamics proteins, including glutaminase-1, are associated with NAC resistance. GSH dynamics is activated in cisplatin-resistant MIBC cells, and combination treatment with a GSH dynamics modulator and cisplatin significantly suppresses tumor growth in an orthotopic xenograft animal model. Collectively, these findings demonstrate the predictive and therapeutic values of GSH dynamics in determining the NAC response in MIBCs.

Keywords:  bladder cancer; combination therapy; digital pathology; glutaminase-1; glutathione; neoadjuvant chemotherapy

DOI:  https://doi.org/10.1016/j.xcrm.2023.101224
Biomater Sci. 2023 Oct 04.

Self-engineered binary nanoassembly enabling closed-loop glutathione depletion-amplified tumor ferroptosis.

Jin Lei, Shenwu Zhang, Zehua Wu, Xinxin Sun, Binghong Zhou, Peiqi Huang, Mingzhu Fang, Lin Li, Cong Luo, Zhonggui He.

Ferroptosis has emerged as a promising target for anticancer treatment, comprising iron-dependent lipid peroxidation and excessive accumulation of reactive oxygen species. Given that glutathione (GSH) overproduced in tumor cells antagonizes the cellular oxidation system, the reduction of GSH production has been extensively explored to induce ferroptosis. However, reducing GSH production alone is insufficient to trigger an intense lipid peroxidation storm. It is highly desirable to achieve systemic GSH depletion through simultaneous production and consumption intervention. Herein, we propose a bidirectional blockage strategy for closed-loop GSH depletion-amplified tumor ferroptosis. Sorafenib (Sor) and gambogic acid (GA) were elaborately fabricated as a self-engineered carrier-free nanoassembly without any nanocarrier materials. The PEGylated dual-drug nanoassembly enables favorable co-delivery and tumor-specific release of Sor and GA. Notably, a closed-loop GSH depletion is observed as a result of a Sor-induced decrease in GSH production and GA-accelerated GSH consumption in vitro and in vivo. As expected, this uniquely engineered dual-drug nanoassembly demonstrates vigorous antitumor activity in 4T1 breast tumor-bearing mice. This study presents a novel nanotherapeutic modality for ferroptosis-driven cancer treatment.

DOI: https://doi.org/10.1039/d3bm01153d
PLoS One. 2023 ;18(10): e0291950

Cystine/Glutamate antiporter system xc- deficiency impairs macrophage glutathione metabolism and cytokine production.

Axel de Baat, Daniel T Meier, Adriano Fontana, Marianne Böni-Schnetzler, Marc Y Donath.

System xc-, encoded by Slc7a11, is an antiporter responsible for exporting glutamate while importing cystine, which is essential for protein synthesis and the formation of thiol peptides, such as glutathione. Glutathione acts as a co-factor for enzymes responsible for scavenging reactive oxygen species. Upon exposure to bacterial products, macrophages exhibit a rapid upregulation of system xc-. This study investigates the impact of Slc7a11 deficiency on the functionality of peritoneal and bone marrow-derived macrophages. Our findings reveal that the absence of Slc7a11 results in significantly reduced glutathione levels, compromised mitochondrial flexibility, and hindered cytokine production in bone marrow-derived macrophages. Conversely, system xc- has a lesser impact on peritoneal macrophages in vivo. These results indicate that system xc- is essential for maintaining glutathione levels, mitochondrial functionality, and cytokine production, with a heightened importance under atmospheric oxygen tension.

DOI: https://doi.org/10.1371/journal.pone.0291950