bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023‒09‒24
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

  1. Open Med (Wars). 2023 ;18(1): 20230756
      Hepatocellular carcinoma (HCC) is a frequently diagnosed malignancy with a high mortality rate. Cisplatin (CDDP) is a widely applied anti-cancer drug. However, a large population of liver cancer patients developed CDDP resistance. The polypyrimidine tract binding protein (PTBP1) is an RNA-binding protein involving in progressions of diverse cancers. Here we report PTBP1 was significantly upregulated in liver tumors and cell lines. Silencing PTBP1 effectively sensitized HCC cells to CDDP. From the established CDDP-resistant HCC cell line (HepG2 CDDP Res), we observed that CDDP-resistant cells were more sensitive to CDDP under low glutamine supply compared with that in HCC parental cells. CDDP-resistant HCC cells displayed elevated glutamine metabolism rate. Consistently, PTBP1 promotes glutamine uptake and the glutamine metabolism key enzyme, glutaminase (GLS) expression. Bioinformatics analysis predicted that the 3'-UTR of GLS mRNA contained PTBP1 binding motifs which were further validated by RNA immunoprecipitation and RNA pull-down assays. PTBP1 associated with GLS 3'-UTR to stabilize GLS mRNA in HCC cells. Finally, we demonstrated that the PTBP1-promoted CDDP resistance of HCC cells was through modulating the GLS-glutamine metabolism axis. Summarily, our findings uncovered a PTBP1-mediated CDDP resistance pathway in HCC, suggesting that PTBP1 is a promisingly therapeutic target to overcome chemoresistance of HCC.
    Keywords:  CDDP resistance; PTBP1; RNA-binding protein; chemosensitivity; glutaminase; glutamine metabolism; hepatocellular carcinoma
  2. Cell Chem Biol. 2023 Sep 21. pii: S2451-9456(23)00284-2. [Epub ahead of print]30(9): 1012-1014
      Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.
  3. Biomed Pharmacother. 2023 Sep 20. pii: S0753-3322(23)01236-2. [Epub ahead of print]167 115438
      Lung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.
    Keywords:  Drug resistance; Gefitinib; Glutamine metabolism; Lung cancer; Sijunzi Tang
  4. Front Immunol. 2023 ;14 1251643
      Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.Methods: In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.
    Results: We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.
    Conclusions: Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.
    Keywords:  SLC7A5; glutamine metabolism; immunotherapy; synergic effect; triple-negative breast cancer
  5. Front Cell Dev Biol. 2023 ;11 1257651
      The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
    Keywords:  Warburg effect; cellular senescence; electron transport chain; mitochondrial integrated stress response; oxidative phosphorylation; respiratory complex III
  6. Cancer Lett. 2023 Sep 20. pii: S0304-3835(23)00347-6. [Epub ahead of print] 216396
      Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy.
    Keywords:  Cancer Metabolism; Cancer nanotechnology; Chemotherapy; Immunotherapy; Tumor microenvironment
  7. Explor Target Antitumor Ther. 2023 ;4(4): 600-615
      Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins' anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential "hallmark of cancer" required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation.
    Keywords:  Aspirin; adjuvant for therapy; anti-tumour; cancer metabolism; cancer prevention; colorectal cancer; metabolic hallmark; nonsteroidal anti-inflammatory drugs
  8. Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984
      Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
    Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment
  9. Front Pharmacol. 2023 ;14 1224828
      Objective: Due to a lack of effective therapy, triple-negative breast cancer (TNBC) is extremely poor prognosis. Metabolic reprogramming is an important hallmark in tumorigenesis, cancer diagnosis, prognosis, and treatment. Categorizing metabolic patterns in TNBC is critical to combat heterogeneity and targeted therapeutics. Methods: 115 TNBC patients from TCGA were combined into a virtual cohort and verified by other verification sets, discovering differentially expressed genes (DEGs). To identify reliable metabolic features, we applied the same procedures to five independent datasets to verify the identified TNBC subtypes, which differed in terms of prognosis, metabolic characteristics, immune infiltration, clinical features, somatic mutation, and drug sensitivity. Results: In general, TNBC could be classified into two metabolically distinct subtypes. C1 had high immune checkpoint genes expression and immune and stromal scores, demonstrating sensitivity to the treatment of PD-1 inhibitors. On the other hand, C2 displayed a high variation in metabolism pathways involved in carbohydrate, lipid, and amino acid metabolism. More importantly, C2 was a lack of immune signatures, with late pathological stage, low immune infiltration and poor prognosis. Interestingly, C2 had a high mutation frequency in PIK3CA, KMT2D, and KMT2C and displayed significant activation of the PI3K and angiogenesis pathways. As a final output, we created a 100-gene classifier to reliably differentiate the TNBC subtypes and AKR1B10 was a potential biomarker for C2 subtypes. Conclusion: In conclusion, we identified two subtypes with distinct metabolic phenotypes, provided novel insights into TNBC heterogeneity, and provided a theoretical foundation for therapeutic strategies.
    Keywords:  immune signature; immunotherapy response; metabolic pathway; metabolic subtypes; mutation landscape; triple-negative breast cancer
  10. Med Rev (Berl). 2021 Dec;1(2): 199-221
      How cells sense and respond to environmental changes is still a key question. It has been identified that cellular metabolism is an important modifier of various epigenetic modifications, such as DNA methylation, histone methylation and acetylation and RNA N6-methyladenosine (m6A) methylation. This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression, and is crucial to regulate cellular homeostasis, cell growth and differentiation. Cancer metabolic reprogramming and epigenetic alterations are widely observed, and facilitate cancer development and progression. In cancer cells, oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the key metabolite levels. In this review, we briefly summarized the current evidence that the abundance of key metabolites, such as S-adenosyl methionine (SAM), acetyl-CoA, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2-HG), uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and lactate, affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer. An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.
    Keywords:  DNA methylation; RNA m6A; cancer metabolic reprogramming; epigenetic modifications; histone acetylation; histone methylation
  11. iScience. 2023 Oct 20. 26(10): 107790
      Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.
    Keywords:  Biochemistry; Cell biology; Cellular physiology; Metabolomics; Molecular physiology
  12. Clin Nutr ESPEN. 2023 Oct;pii: S2405-4577(23)01223-8. [Epub ahead of print]57 730-734
      BACKGROUND & AIMS: The current standard treatment modality for advanced head and neck squamous cell carcinoma (HNSCC), namely platinum-based (PB) concurrent chemoradiotherapy (CRT), is associated with frequent severe mucositis which is responsible for the multiple acute and late adverse events. So far, effective preventive methods for this CRT-induced mucositis are not identified. In the current study, we examined the prophylactic effects of beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) (HMB/Arg/Gln) mixture.METHODS: Patients with HNSCC who were subject to PBCRT were randomly assigned to HMB/Arg/Gln intervention (Group I) and non-intervention (Group NI) cohort. The incidences of ≧ grade 3 mucositis (primary endpoint), ≧ grade 2 mucositis, and opioid usage and the degree of body weight loss (secondary endpoints) were compared between Group I and Group NI.
    RESULTS: A total of 75 patients were enrolled to this study and 38 patients were assigned to Group I, while 37 patients were to Group NI. After excluding patients who failed to complete CRT (3 in Group I and 2 in Group NI) or withdrew consents (11 in Group I and 1 in Group NI), 24 patients in Group I and 34 patients in Group NI were evaluated. HMB/Arg/Gln failed to reduce the incidences of ≧ grade 2 mucositis, but significantly (p = 0.0003) inhibited grade 3 mucositis in the late phase CRT, reducing the incidence from 64.6% (Group NI) to 25% (Group I) at 70Gy. The degree of body weight loss was significantly (p = 0.0038) lower in Group I (5.6%) compared to Group NI (8.9%), preventing the progression of PBCRT-induced cachexia.
    CONCLUSIONS: HMB/Arg/Gln administration demonstrated inhibitory effects on the progression of grade 3 mucositis and cancer cachexia in HNSCC patients treated with PBCRT. A larger scale phase III study is encouraged.
    CLINICAL TRIAL REGISTRATION: This study is registered to the UMIN Clinical Trial Registry: UMIN000050011.
    Keywords:  Arginine (Arg); Beta-hydroxy-beta-methylbutyrate (HMB); Glutamine (Gln) (HMB/Arg/Gln) mixture; Head and neck squamous cell carcinoma; Mucositis; Platinum-based concurrent chemoradiotherapy; Prevention
  13. Free Radic Biol Med. 2023 Sep 20. pii: S0891-5849(23)00644-5. [Epub ahead of print]
      Gamma-glutamyl transpeptidase (GGT) is an enzyme located on the outer membrane of the cells where it regulates the metabolism of glutathione (GSH), the most abundant intracellular antioxidant thiol. GGT plays a key role in the control of redox homeostasis, by hydrolyzing extracellular GSH and providing the cell with the recovery of cysteine, which is necessary for de novo intracellular GSH and protein biosynthesis. Therefore, the upregulation of GGT confers to the cell greater resistance to oxidative stress and the advantage of growing fast. Indeed, GGT is upregulated in inflammatory conditions and in the progression of various human tumors and it is involved in many physiological disorders related to oxidative stress, such as cardiovascular disease and diabetes. Currently, GGT is considered a marker of liver damage, cancer, and low-grade chronic inflammation. This review addresses the current knowledge on the structure-function relationship of GGT, focusing on human GGT, and provides information on the pleiotropic biological role and relevance of the enzyme as a target of drugs aimed at alleviating oxidative stress-related diseases. The development of new GGT inhibitors is critically discussed, as are the advantages and disadvantages of their potential use in clinics. Considering its pleiotropic activities and evolved functions, GGT is a potential "moonlighting protein".
    Keywords:  GGT inhibitors; Gamma-glutamyl transpeptidase; Glutathione; Oxidative stress; Redox homeostasis
  14. Sci Total Environ. 2023 Sep 14. pii: S0048-9697(23)05664-4. [Epub ahead of print]905 167039
      Cadmium (Cd), a predominant environmental pollutant, is a canonical toxicant that acts on the kidneys. However, the nephrotoxic effect and underlying mechanism activated by chronic exposure to Cd remain unclear. In the present study, male mice (C57BL/6J, 8 weeks) were treated with 0.6 mg/L cadmium chloride (CdCl2) administered orally for 6 months, and tubular epithelial cells (TCMK-1 cells) were treated with low-dose (1, 2, and 3 μM) CdCl2 for 72 h (h). Our study results revealed that environmental Cd exposure triggered ferroptosis and renal dysfunction. Spatially resolved metabolomics enabled delineation of metabolic profiles and visualization of the disruption to glutathione homeostasis related to ferroptosis in mouse kidneys. Multiomics analysis revealed that chronic Cd exposure induced glutathione redox imbalance that depended on STEAP3-driven lysosomal iron overload. In particular, glutathione metabolic reprogramming linked to ferroptosis emerged as a metabolic hallmark in the blood of Cd-exposed workers. In conclusion, this study provides the first evidence indicating that chronic Cd exposure triggers ferroptosis and renal dysfunction that depend on STEAP3-mediated glutathione redox imbalance, greatly increasing our understanding of the metabolic reprogramming induced by Cd exposure in the kidneys and providing novel clues linking chronic Cd exposure to nephrotoxicity.
    Keywords:  Cadmium; Ferroptosis; Glutathione redox imbalance; Kidney damage; STEAP3