bims-glucam 2024-10-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–10–27
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine sensing licenses cholesterol synthesis.
GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.
Enhancing GFPT1 expression with glutamine protects chondrocytes in osteoarthritis.
Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.
Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism.
A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.
Metabolism: an important player in glioma survival and development.
Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2.
Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.
A novel, glutathione-activated prodrug of pimasertib loaded in liposomes for targeted cancer therapy.
Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells.

EMBO J. 2024 Oct 21.

Glutamine sensing licenses cholesterol synthesis.

Bruna Martins Garcia, Philipp Melchinger, Tania Medeiros, Sebastian Hendrix, Kavan Prabhu, Mauro Corrado, Jenina Kingma, Andrej Gorbatenko, Soni Deshwal, Matteo Veronese, Luca Scorrano, Erika Pearce, Patrick Giavalisco, Noam Zelcer, Lena Pernas.

  The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.

Keywords:  Cholesterol; HMGCR; MFN2; Nutrient Sensing; SREBP2

DOI:  https://doi.org/10.1038/s44318-024-00269-0
Neuro Oncol. 2024 Oct 24. pii: noae222. [Epub ahead of print]

GDH1-catalytic glutaminolysis feedback activate EGFR/PI3K/AKT pathway and reprogram glioblastoma metabolism.

Rui Yang, Guanghui Zhang, Zhen Meng, Li Wang, Yanping Li, Haibin Li, Siyuan Yan, Xiaonan Wei, Shanshan Wang, Hongjuan Cui.

   BACKGROUND: Glutamine is an important nutriment for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.
METHODS: Knockdown and overexpression cells were obtained to explore the functional roles of GDH1 in cell proliferation, tumor formation and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay and western blot were performed to verify the regulation of EGFR-AKT pathway by the glutamate dehydrogenase 1 (GDH1, also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.
RESULTS: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3, and then promotes the activation of PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays important roles in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose condition dependent on KDM6A-mediated demethylation of H3K27.
CONCLUSION: These findings suggest a novel function of glutaminolysis in regulation of signal transduction and metabolism reprograming, provide further evidence for unique role of glutaminolysis in GBM progression.

Keywords:  EGFR-AKT pathway; GBM; GDH1; KDM6A; metabolism reprogramming

DOI:  https://doi.org/10.1093/neuonc/noae222
Int Immunopharmacol. 2024 Oct 18. pii: S1567-5769(24)01949-0. [Epub ahead of print]143(Pt 2): 113427

Enhancing GFPT1 expression with glutamine protects chondrocytes in osteoarthritis.

Zhao Zhang, Xinyu Li, Weihua Guo, Zeyu Huang.

   OBJECTIVE: Osteoarthritis (OA) is the leading joint disease without currently available disease-modified drugs. The current study aimed to identify potential drug targets that could decelerate the progression of OA.
METHODS: We employed Mendelian Randomization (MR) and colocalization analysis to identify therapeutic targets linked to 12 OA traits within 2645 targets. Bulk and single-cell RNA-seq analyses of cartilage samples were conducted to pinpoint GFPT1 and determine the specific cell types in which GFPT1 is expressed. Overexpression and knockdown experiments further explored the expression and potential OA-associated functions of GFPT1.
RESULTS: GFPT1 has been identified as a cross-OA therapeutic candidate gene by MR analysis. We observed a significant reduction in GFPT1 expression in OA cartilage compared to normal cartilage from public transcriptomic data of both humans and mice. In vitro experiments confirmed these findings at both mRNA and protein levels in OA chondrocytes. IL-1β stimulation leads to downregulation of GFPT1. We confirmed that supplementary glutamine can reverse the suppression of GFPT1 more effectively than glucosamine in the OA in vitro model. GFPT1 upregulation with glutamine, in turn, further increases the expression of COL2A1 and decreases the expression of MMP13.
CONCLUSIONS: Our findings demonstrate that GFPT1 is downregulated in OA, and overexpressing GFPT1 can restore the anabolic metabolism of cartilage. Compared to glucosamine, enhancing GFPT1 expression with glutamine to influence the hexosamine biosynthetic pathway may offer a more effective therapeutic strategy for OA.

Keywords:  Anabolic metabolism; GFPT1; HBP; Mendelian randomization; Osteoarthritis; scRNA-seq

DOI:  https://doi.org/10.1016/j.intimp.2024.113427
Cells. 2024 Oct 17. pii: 1721. [Epub ahead of print]13(20):

Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.

Xingyu Chen, Zihan Wang, Bo Zhu, Min Deng, Jiayue Qiu, Yunwen Feng, Ning Ding, Chen Huang.

  Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy.

Keywords:  aging; glioma; metabolic plasticity; metabolic reprogramming; pan-cancer; scRNA sequencing analysis; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cells13201721
Pathogens. 2024 Oct 03. pii: 867. [Epub ahead of print]13(10):

Transcriptomic and Proteomic Insights into Host Immune Responses in Pediatric Severe Malarial Anemia: Dysregulation in HSP60-70-TLR2/4 Signaling and Altered Glutamine Metabolism.

Clinton O Onyango, Samuel B Anyona, Ivy Hurwitz, Evans Raballah, Sharely A Wasena, Shamim W Osata, Philip Seidenberg, Benjamin H McMahon, Christophe G Lambert, Kristan A Schneider, Collins Ouma, Qiuying Cheng, Douglas J Perkins.

  Severe malarial anemia (SMA, Hb < 6.0 g/dL) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission zones. This study explored the entire expressed human transcriptome in whole blood from 66 Kenyan children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25), focusing on host immune response networks. RNA-seq analysis revealed 6862 differentially expressed genes, with equally distributed up-and down-regulated genes, indicating a complex host immune response. Deconvolution analyses uncovered leukocytic immune profiles indicative of a diminished antigenic response, reduced immune priming, and polarization toward cellular repair in SMA. Weighted gene co-expression network analysis revealed that immune-regulated processes are central molecular distinctions between non-SMA and SMA. A top dysregulated immune response signaling network in SMA was the HSP60-HSP70-TLR2/4 signaling pathway, indicating altered pathogen recognition, innate immune activation, stress responses, and antigen recognition. Validation with high-throughput gene expression from a separate cohort of Kenyan children (n = 50) with varying severities of malarial anemia (n = 38 non-SMA and n = 12 SMA) confirmed the RNA-seq findings. Proteomic analyses in 35 children with matched transcript and protein abundance (n = 19 non-SMA and n = 16 SMA) confirmed dysregulation in the HSP60-HSP70-TLR2/4 signaling pathway. Additionally, glutamine transporter and glutamine synthetase genes were differentially expressed, indicating altered glutamine metabolism in SMA. This comprehensive analysis underscores complex immune dysregulation and novel pathogenic features in SMA.

Keywords:  RNA-seq; childhood innate immunity; differential gene expression; glutamine synthetase; glutamine transporters; heat shock proteins; host immune response; proteomics; toll-like receptors

DOI:  https://doi.org/10.3390/pathogens13100867
Int J Biol Sci. 2024 ;20(13): 5109-5126

A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.

Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi.

  Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

Keywords:  Epithelial-mesenchymal transition; Metabolism; Tumor cells; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.99680
EBioMedicine. 2024 Oct 21. pii: S2352-3964(24)00411-0. [Epub ahead of print]109 105375

SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.

Haoran Feng, Junxian Yu, Zhuoqing Xu, Qingqing Sang, Fangyuan Li, Mengdi Chen, Yunqin Chen, Beiqin Yu, Nan Zhu, Jiazeng Xia, Changyu He, Junyi Hou, Xiongyan Wu, Chao Yan, Zhenggang Zhu, Liping Su, Jianfang Li, Wentao Dai, Yuan-Yuan Li, Bingya Liu.

   BACKGROUND: SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.
METHODS: Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.
FINDINGS: Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.
INTERPRETATION: SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.
FUNDING: This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.

Keywords:  Ferroptosis; GPX4; Gastric cancer; Glutathione metabolism; SLC7A9

DOI:  https://doi.org/10.1016/j.ebiom.2024.105375
Discov Oncol. 2024 Oct 22. 15(1): 577

Metabolism: an important player in glioma survival and development.

Ning Wang, Yiru Yuan, Tianhao Hu, Huizhe Xu, Haozhe Piao.

  Gliomas are malignant tumors originating from both neuroglial cells and neural stem cells. The involvement of neural stem cells contributes to the tumor's heterogeneity, affecting its metabolic features, development, and response to therapy. This review provides a brief introduction to the importance of metabolism in gliomas before systematically categorizing them into specific groups based on their histological and molecular genetic markers. Metabolism plays a critical role in glioma biology, as tumor cells rely heavily on altered metabolic pathways to support their rapid growth, survival, and progression. Dysregulated metabolic processes, involving carbohydrates, lipids, and amino acids not only fuel tumor development but also contribute to therapy resistance and metastatic potential. By understanding these metabolic changes, key intervention points, such as mutations in genes like RTK, EGFR, RAS, and IDH can be identified, paving the way for novel therapeutic strategies. This review emphasizes the connection between metabolic pathways and clinical challenges, offering actionable insights for future research and therapeutic development in gliomas.

Keywords:  Gliomas; Glucose metabolism; Lipid metabolism; Metabolisms; Signaling pathway; Treatment directions

DOI:  https://doi.org/10.1007/s12672-024-01402-5
Amino Acids. 2024 Oct 19. 56(1): 64

Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2.

Sebastian Jakobsen, Maria Pedersen, Carsten Uhd Nielsen.

  The sodium-coupled neutral amino acid transporter SNAT2 (SLC38A2) has been shown to have important physiological functions and is implicated in various diseases like cancer. However, few compounds targeting this transporter have been identified and little is known about the structural requirements for SNAT2 binding. In this study, the aim was to establish the basic structure-activity relationship for SNAT2 using amino acid analogs. These analogs were first studied for their ability to inhibit SNAT2-mediated 3H-glycine uptake in hyperosmotically treated PC-3 cells. Then to identify substrates a FLIPR membrane potential assay and o-phthalaldehyde derivatization of intracellular amino with subsequent quantification using HPLC-Fl was used. The results showed that ester derivatives of the C-terminus maintained SNAT2 affinity, suggesting that the negative charge was less important. On the other hand, the positive charge at the N-terminus of the substrate and the ability to donate at least two hydrogen bonds to the binding site appeared important for SNAT2 recognition of the amine. Side chain charged amino acids generally had no affinity for SNAT2, but their non-charged derivatives were able to inhibit SNAT2-mediated 3H-glycine uptake, while also showing that amino acids of a notable length still had affinity for SNAT2. Several amino acid analogs appeared to be novel substrates of SNAT2, while γ-benzyl L-glutamate seemed to be inefficiently translocated by SNAT2. Elaborating on this structure could lead to the discovery of non-translocated inhibitors of SNAT2. Thus, the present study provides valuable insights into the basic structural binding requirements for SNAT2 and can aid the future discovery of compounds that target SNAT2.

Keywords:  Amino acid analogs; Amino acid transporter; FMP assay; PC-3; SNAT2; Structure-activity relationship

DOI:  https://doi.org/10.1007/s00726-024-03424-3
Cell Metab. 2024 Oct 18. pii: S1550-4131(24)00395-4. [Epub ahead of print]

Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Chenxi Zhao, Tingting Zhang, Si-Tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li.

  Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.

Keywords:  ARF1; GSH; SCARB2; adipocyte; breast cancer; glutathione; lysosomal integral membrane protein-2; mTORC1; mammalian target of rapamycin complex 1; obesity

DOI:  https://doi.org/10.1016/j.cmet.2024.09.013
RSC Med Chem. 2024 Oct 03.

A novel, glutathione-activated prodrug of pimasertib loaded in liposomes for targeted cancer therapy.

Arianna Amenta, Susanna Comi, Marcelo Kravicz, Silvia Sesana, Antonia Antoniou, Daniele Passarella, Pierfausto Seneci, Sara Pellegrino, Francesca Re.

Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its in vitro biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug.

DOI: https://doi.org/10.1039/d4md00517a
FEBS J. 2024 Oct 21.

Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells.

Ling Wang, Shibo Sun, Haowen Liu, Qiuyu Zhang, Yao Meng, Fan Sun, Jianjun Zhang, Haiyan Liu, Weiping Xu, Zhiwei Ye, Jie Zhang, Bingbing Sun, Jianqiang Xu.

  Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx, was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and β-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.

Keywords:  disulfide stress; gastric cancer cell; glaucocalyxin A (GlauA); glutathione; selenocysteine; thioredoxin reductase 1 (TXNRD1)

DOI:  https://doi.org/10.1111/febs.17301