bims-glucam 2024-07-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒07‒21
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells.
LncRNA FEZF1-AS1 facilitates cisplatin resistance in non-small cell lung cancer through modulating the miR-32-5p-glutaminase axis.
Asparagine: A key metabolic junction in targeted tumor therapy.
Imaging Tumor Metabolism.
Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers.
Mitochondrial inhibitors: a new horizon in breast cancer therapy.
Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.
Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.
Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.
Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.
Amino acid deprivation in cancer cells with compensatory autophagy induction increases sensitivity to autophagy inhibitors.
Untargeted metabolomics analysis of serum and urine unveils the protective effect of cilastatin on altered metabolic pathways during cisplatin-induced acute kidney injury.

NPJ Syst Biol Appl. 2024 Jul 18. 10(1): 77

Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells.

Jan Ewald, Ziyang He, Wassili Dimitriew, Stefan Schuster.

Energy metabolism is crucial for all living cells, especially during fast growth or stress scenarios. Many cancer and activated immune cells (Warburg effect) or yeasts (Crabtree effect) mostly rely on aerobic glucose fermentation leading to lactate or ethanol, respectively, to generate ATP. In recent years, several mathematical models have been proposed to explain the Warburg effect on theoretical grounds. Besides glucose, glutamine is a very important substrate for eukaryotic cells-not only for biosynthesis, but also for energy metabolism. Here, we present a minimal constraint-based stoichiometric model for explaining both the classical Warburg effect and the experimentally observed respirofermentation of glutamine (WarburQ effect). We consider glucose and glutamine respiration as well as the respective fermentation pathways. Our resource allocation model calculates the ATP production rate, taking into account enzyme masses and, therefore, pathway costs. While our calculation predicts glucose fermentation to be a superior energy-generating pathway in human cells, different enzyme characteristics in yeasts reduce this advantage, in some cases to such an extent that glucose respiration is preferred. The latter is observed for the fungal pathogen Candida albicans, which is a known Crabtree-negative yeast. Further, optimization results show that glutamine is a valuable energy source and important substrate under glucose limitation, in addition to its role as a carbon and nitrogen source of biomass in eukaryotic cells. In conclusion, our model provides insights that glutamine is an underestimated fuel for eukaryotic cells during fast growth and infection scenarios and explains well the observed parallel respirofermentation of glucose and glutamine in several cell types.

DOI: https://doi.org/10.1038/s41540-024-00393-x
Am J Cancer Res. 2024 ;14(6): 3153-3170

LncRNA FEZF1-AS1 facilitates cisplatin resistance in non-small cell lung cancer through modulating the miR-32-5p-glutaminase axis.

Wei Lin, Wei-Chun Wu, Zhi Liang, Jian-Hao Zhang, Shi-Peng Fang.

  Non-small cell lung cancer (NSCLC) is one of the prevalent malignancies. Cisplatin (CDDP) is a conventional chemotherapeutic agent against NSCLC. However, inherent and acquired chemoresistance limited the effectiveness of cisplatin in treatment of NSCLC. This study aimed to investigate the roles and underlying mechanisms of lncRNA-FEZF1-AS1 in mediating cisplatin sensitivity in NSCLC. We found that FEZF1-AS1 levels were significantly higher in lung cancer patients and cell lines. Blocking FEZF1-AS1 sensitized lung cancer cells to cisplatin. Additionally, both glutamine metabolism and FEZF1-AS1 were significantly elevated in cisplatin resistant NSCLC cell lines, A549/CDDP R and SK-MES-1 CDDP/R. Analysis using bioinformatics, RNA pull-down assay and luciferase assay demonstrated that FEZF1-AS1 sponged miR-32-5p, which acted as a tumor suppressor in NSCLC. Glutaminase (GLS), a key enzyme in the glutamine metabolism, was predicted and validated as the direct target of miR-32-5p in NSCLC cells. Inhibiting glutamine metabolism or reducing glutamine supply effectively resensitized cisplatin-resistant cells. Furthermore, restoring miR-32-5p in FEZF1-AS1-overexpressing cisplatin resistant cells successfully overcame FEZF1-AS1-mediated cisplatin resistance by targeting GLS. These findings were further supported by in vivo xenograft mice experiments. This study uncovered the roles and molecular mechanisms of lncRNA FEZF1-AS1 in mediating cisplatin resistance in NSCLC, specifically through modulating the miR-32-5p-GLS axis, providing support for the development of new therapeutic approaches against chemoresistant lung cancer.

Keywords:  GLS; Non-small cell lung cancer; cisplatin resistance; glutamine metabolism; lncRNA-FEZF1-AS1; miR-32a-5p

DOI:  https://doi.org/10.62347/WUKN6549
Pharmacol Res. 2024 Jul 14. pii: S1043-6618(24)00237-8. [Epub ahead of print]206 107292

Asparagine: A key metabolic junction in targeted tumor therapy.

Xuan Wang, Weijian Gong, Xueyou Xiong, Xuemei Jia, Juan Xu.

  Nutrient bioavailability in the tumor microenvironment plays a pivotal role in tumor proliferation and metastasis. Among these nutrients, glutamine is a key substance that promotes tumor growth and proliferation, and its downstream metabolite asparagine is also crucial in tumors. Studies have shown that when glutamine is exhausted, tumor cells can rely on asparagine to sustain their growth. Given the reliance of tumor cell proliferation on asparagine, restricting its bioavailability has emerged as promising strategy in cancer treatment. For instance, the use of asparaginase, an enzyme that depletes asparagine, has been one of the key chemotherapies for acute lymphoblastic leukemia (ALL). However, tumor cells can adapt to asparagine restriction, leading to reduced chemotherapy efficacy, and the mechanisms by which different genetically altered tumors are sensitized or adapted to asparagine restriction vary. We review the sources of asparagine and explore how limiting its bioavailability impacts the progression of specific genetically altered tumors. It is hoped that by targeting the signaling pathways involved in tumor adaptation to asparagine restriction and certain factors within these pathways, the issue of drug resistance can be addressed. Importantly, these strategies offer precise therapeutic approaches for genetically altered cancers.

Keywords:  Asparaginase (Pubchem CID: 436058); Asparagine; Asparagine synthetase (Pubchem CID: 381121140); Aspartic acid (Pubchem CID: 5960); Cancer; Genetic Alteration; Glutamic acid (Pubchem CID: 33032); Glutaminase (Pubchem CID: 72950407); Glutamine (Pubchem CID: 5961); Histidine (Pubchem CID: 6274); L-asparagine (Pubchem CID: 6267); Metabolism; Serine (Pubchem CID: 5951); Targeted therapy; Threonine (Pubchem CID: 6288)

DOI:  https://doi.org/10.1016/j.phrs.2024.107292
Cold Spring Harb Perspect Med. 2024 Jul 15. pii: a041551. [Epub ahead of print]

Imaging Tumor Metabolism.

Thomas Ruan, Kayvan R Keshari.

Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.

DOI: https://doi.org/10.1101/cshperspect.a041551
Mini Rev Med Chem. 2024 ;24(12): 1187-1202

Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers.

Diana Xochiquetzal Robledo-Cadena, Silvia Cecilia Pacheco-Velazquez, Jorge Luis Vargas-Navarro, Joaquín Alberto Padilla-Flores, Rafael Moreno-Sanchez, Sara Rodríguez-Enríquez.

  Accelerated aerobic glycolysis is one of the main metabolic alterations in cancer, associated with malignancy and tumor growth. Although glycolysis is one of the most studied properties of tumor cells, recent studies demonstrate that oxidative phosphorylation (OxPhos) is the main ATP provider for the growth and development of cancer. In this last regard, the levels of mRNA and protein of OxPhos enzymes and transporters (including glutaminolysis, acetate and ketone bodies catabolism, free fatty acid β-oxidation, Krebs Cycle, respiratory chain, phosphorylating system- ATP synthase, ATP/ADP translocator, Pi carrier) are altered in tumors and cancer cells in comparison to healthy tissues and organs, and non-cancer cells. Both energy metabolism pathways are tightly regulated by transcriptional factors, oncogenes, and tumor-suppressor genes, all of which dictate their protein levels depending on the micro-environmental conditions and the type of cancer cell, favoring cancer cell adaptation and growth. In the present review paper, variation in the mRNA and protein levels as well as in the enzyme/ transporter activities of the OxPhos machinery is analyzed. An integral omics approach to mitochondrial energy metabolism pathways may allow for identifying their use as suitable, reliable biomarkers for early detection of cancer development and metastasis, and for envisioned novel, alternative therapies.

Keywords:  Metabolic biomarker; anti-mitochondrial therapy.; cancer mitochondria; mitochondrial proteins; oxidative phosphorylation

DOI:  https://doi.org/10.2174/0113895575254320231030051124
Front Pharmacol. 2024 ;15 1421905

Mitochondrial inhibitors: a new horizon in breast cancer therapy.

Yalan Yan, Sijie Li, Lanqian Su, Xinrui Tang, Xiaoyan Chen, Xiang Gu, Guanhu Yang, Hao Chi, Shangke Huang.

  Breast cancer, due to resistance to standard therapies such as endocrine therapy, anti-HER2 therapy and chemotherapy, continues to pose a major health challenge. A growing body of research emphasizes the heterogeneity and plasticity of metabolism in breast cancer. Because differences in subtypes exhibit a bias toward metabolic pathways, targeting mitochondrial inhibitors shows great potential as stand-alone or adjuvant cancer therapies. Multiple therapeutic candidates are currently in various stages of preclinical studies and clinical openings. However, specific inhibitors have been shown to face multiple challenges (e.g., single metabolic therapies, mitochondrial structure and enzymes, etc.), and combining with standard therapies or targeting multiple metabolic pathways may be necessary. In this paper, we review the critical role of mitochondrial metabolic functions, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle, and fatty acid and amino acid metabolism, in metabolic reprogramming of breast cancer cells. In addition, we outline the impact of mitochondrial dysfunction on metabolic pathways in different subtypes of breast cancer and mitochondrial inhibitors targeting different metabolic pathways, aiming to provide additional ideas for the development of mitochondrial inhibitors and to improve the efficacy of existing therapies for breast cancer.

Keywords:  breast cancer; cancer subtype; metabolic reprogramming; mitochondrial inhibitors; tumor progression

DOI:  https://doi.org/10.3389/fphar.2024.1421905
Nat Metab. 2024 Jul 15.

Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.

Simon Lecoutre, Salwan Maqdasy, David Rizo-Roca, Gianluca Renzi, Ivan Vlassakev, Lynn M Alaeddine, Romane Higos, Jutta Jalkanen, Jiawei Zhong, Danae S Zareifi, Scott Frendo-Cumbo, Lucas Massier, Ondrej Hodek, Marta Juvany, Thomas Moritz, Thais de Castro Barbosa, Muhmmad Omar-Hmeadi, Marta López-Yus, Fatiha Merabtene, Jimon Boniface Abatan, Geneviève Marcelin, Elie-Julien El Hachem, Christine Rouault, Martin O Bergo, Paul Petrus, Juleen R Zierath, Karine Clément, Anna Krook, Niklas Mejhert, Mikael Rydén.

Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.

DOI: https://doi.org/10.1038/s42255-024-01083-y
Cancer Res. 2024 Jul 15. 84(14): 2297-2312

Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia.

Thorsten Neuß, Min-Chun Chen, Nils Wirges, Sinem Usluer, Rupert Oellinger, Svenja Lier, Michael Dudek, Tobias Madl, Martin Jastroch, Katja Steiger, Werner Schmitz, Henrik Einwächter, Roland M Schmid.

Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2213
bioRxiv. 2024 Jul 12. pii: 2024.07.09.602707. [Epub ahead of print]

Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.

Nidhi Raghuram, Adam Hughes.

Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism.

DOI: https://doi.org/10.1101/2024.07.09.602707
Cancer Res. 2024 Jul 18.

Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.

Jianqiang Yang, Fanghui Chen, Liwei Lang, Fan Yang, Zhenzhen Fu, Juan Martínez, Amber Cho, Nabil F Saba, Yong Teng.

Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. Here, we conducted a bioinformatic analysis of the TCGA HNSCC cohort that revealed a robust correlation between expression of c-Myc and GLS1, which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a USP1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced ACC-dependent SLUG acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0254
Mol Cell Oncol. 2024 ;11(1): 2377404

Amino acid deprivation in cancer cells with compensatory autophagy induction increases sensitivity to autophagy inhibitors.

Takahito Fukui, Manami Yabumoto, Misuzu Nishida, Shiori Hirokawa, Riho Sato, Taichi Kurisu, Miyu Nakai, Md Abul Hassan, Koji Kishimoto.

  Inhibition of autophagy is an important strategy in cancer therapy. However, prolonged inhibition of certain autophagies in established cancer cells may increase therapeutic resistance, though the underlying mechanisms of its induction and enhancement remain unclear. This study sought to elucidate the mechanisms of therapeutic resistance through repeated autophagy inhibition and amino acid deprivation (AD) in an in vitro model of in vivo chronic nutrient deprivation associated with cancer cell treatment. In the human cervical cancer cell line HeLa and human breast cancer cell line MCF-7, initial extracellular AD induced the immediate expression of endosomal microautophagy (eMI). However, repeated inhibition of eMI with U18666A and extracellular AD induced macroautophagy (MA) to compensate for reduced eMI, simultaneously decreasing cytotoxicity. Here, hyperphosphorylated JNK was transformed into a hypophosphorylated state, suggesting conversion of the cell death signal to a survival signal. In a nutrient medium, cell death could not be induced by MA inhibition. However, since LAT1 inhibitors induce intracellular AD, combining them with MA and eMI inhibitors successfully promoted cell death in resistant cells. Our study identified a novel therapeuic approach for promoting cell death and addressing therapeutic resistance in cancers under autophagy-inhibitor treatment.

Keywords:  Amino acid deprivation; amino acid transporter; autophagy; cancer; chemoresistance

DOI:  https://doi.org/10.1080/23723556.2024.2377404
Biochem Pharmacol. 2024 Jul 16. pii: S0006-2952(24)00418-0. [Epub ahead of print] 116435

Untargeted metabolomics analysis of serum and urine unveils the protective effect of cilastatin on altered metabolic pathways during cisplatin-induced acute kidney injury.

Estefanía Moreno-Gordaliza, M Ángeles González-Nicolás, Alberto Lázaro, Coral Barbas, M Milagros Gómez-Gómez, Ángeles López-Gonzálvez.

  Acute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.

Keywords:  Biomarkers; Cilastatin; Cisplatin; Metabolomics; Nephroprotection; Nephrotoxicity

DOI:  https://doi.org/10.1016/j.bcp.2024.116435