bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–01–22
eight papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer.
  2. Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells.
  3. Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review.
  4. Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.
  5. High-dose oral glutamine can reduce CSF glutamate in MELAS without a beneficial clinical or cerebral tissue effect.
  6. The potential of glutamine metabolism-related long non-coding RNAs (lncRNAs) as prognostic biomarkers in multiple myeloma patients.
  7. A prospective case-cohort analysis of plasma metabolites and breast cancer risk.
  8. Fasting and fasting mimicking diets in cancer prevention and therapy.
  1. Cancer Lett. 2023 Jan 13. pii: S0304-3835(23)00015-0. [Epub ahead of print]556 216064
    The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer.
    Wei Jiang, Xueyan Ouyang, Zhaodong Ji, Wanling Shi, Yutuan Wu, Qianlan Yao, Yi Wang, Wentao Yang, Libing Xiang, Huijuan Yang.
      The mutation of glutamic acid 545 to lysine (E545K) in PIK3CA, as the most common missense mutation of this gene in various cancer types, is frequently observed in cervical cancer and has been shown to reduce cervical cancer radiosensitivity. However, the underlying mechanisms remain unclear. Here, we implicate the alterations of glutamine metabolism in PIK3CA-E545K-mediated radioresistance of cervical cancer. Specifically, PIK3CA mutation negatively regulated the expression of SIRT4 via the epigenetic regulator EP300 independently of the canonical mTORC1 pathway. PIK3CA-E545K-induced SIRT4 downregulation promoted cell proliferation, migration, and radiation-induced DNA repair and apoptosis, while SIRT4 overexpression reversed the radioresistance phenotype mediated by PIK3CA mutation. Mechanistically, SIRT4 modulated glutamine metabolism and thus cellular apoptosis by negatively regulating a glutamate pyruvate transaminase GPT1. Moreover, the PI3K inhibitor BYL719, but not mTOR inhibitors, exerted remarkable synergistic effects with radiotherapy by inhibiting glutamine metabolism in vitro and in vivo. Collectively, this study reveals the role of PIK3CA-E545K-SIRT4 axis in regulating glutamine metabolism and the radioresistance in cervical cancer, which provides a necessary preliminary basis for clinical research of PI3K inhibitors as radiosensitizing agents.
    Keywords:  Cervical cancer; GPT1; Glutamine metabolism; PIK3CA-E545K mutation; Radiosensitivity; SIRT4
    DOI:  https://doi.org/10.1016/j.canlet.2023.216064
  2. Antioxidants (Basel). 2022 Dec 26. pii: 43. [Epub ahead of print]12(1):
    Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells.
    Cecilia Marini, Vanessa Cossu, Sonia Carta, Elisa Greotti, Daniela Gaglio, Nadia Bertola, Sabrina Chiesa, Silvia Bruno, Francesca Vitale, Marcella Bonanomi, Danilo Porro, Mattia Riondato, Anna Maria Orengo, Matteo Bauckneht, Silvia Morbelli, Silvia Ravera, Gianmario Sambuceti.
      Cancer utilization of large glutamine equivalents contributes to diverging glucose-6-P flux toward the pentose phosphate shunt (PPP) to feed the building blocks and the antioxidant responses of rapidly proliferating cells. In addition to the well-acknowledged cytosolic pathway, cancer cells also run a largely independent PPP, triggered by hexose-6P-dehydrogenase within the endoplasmic reticulum (ER), whose activity is mandatory for the integrity of ER-mitochondria networking. To verify whether this reticular metabolism is dependent on glutamine levels, we complemented the metabolomic characterization of intermediates of the glucose metabolism and tricarboxylic acid cycle with the estimation of proliferating activity, energy metabolism, redox damage, and mitochondrial function in two breast cancer cell lines. ER-PPP activity and its determinants were estimated by the ER accumulation of glucose analogs. Glutamine shortage decreased the proliferation rate despite increased ATP and NADH levels. It depleted NADPH reductive power and increased malondialdehyde content despite a marked increase in glucose-6P-dehydrogenase. This paradox was explained by the deceleration of ER-PPP favored by the decrease in hexose-6P-dehydrogenase expression coupled with the opposite response of its competitor enzyme glucose-6P-phosphatase. The decreased ER-PPP activity eventually hampered mitochondrial function and calcium exchanges. These data configure the ER-PPP as a powerful, unrecognized regulator of cancer cell metabolism and proliferation.
    Keywords:  18F-fluoro-deoxy-glucose; breast cancer; calcium flux; endoplasmic reticulum; endoplasmic reticulum–mitochondria network; glutamine metabolism; hexose-6-phosphate-dehydrogenase; pentose phosphate pathway; redox balance
    DOI:  https://doi.org/10.3390/antiox12010043
  3. Cancers (Basel). 2023 Jan 08. pii: 411. [Epub ahead of print]15(2):
    Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review.
    Graziantonio Lauria, Rosita Curcio, Paola Lunetti, Stefano Tiziani, Vincenzo Coppola, Vincenza Dolce, Giuseppe Fiermonte, Amer Ahmed.
      Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming is a hallmark of PDAC. Glucose and glutamine metabolism are extensively rewired in order to fulfil both energetic and synthetic demands of this aggressive tumour and maintain favorable redox homeostasis. The mitochondrial pyruvate carrier (MPC), the glutamine carrier (SLC1A5_Var), the glutamate carrier (GC), the aspartate/glutamate carrier (AGC), and the uncoupling protein 2 (UCP2) have all been shown to influence PDAC cell growth and progression. The expression of MPC is downregulated in PDAC and its overexpression reduces cell growth rate, whereas the other four transporters are usually overexpressed and the loss of one or more of them renders PDAC cells unable to grow and proliferate by altering the levels of crucial metabolites such as aspartate. The aim of this review is to comprehensively evaluate the current experimental evidence about the function of these carriers in PDAC metabolic rewiring. Dissecting the precise role of these transporters in the context of the tumour microenvironment is necessary for targeted drug development.
    Keywords:  PDAC; aspartate; glutamine; metabolic rewiring; mitochondrial carriers
    DOI:  https://doi.org/10.3390/cancers15020411
  4. Cancers (Basel). 2023 Jan 15. pii: 531. [Epub ahead of print]15(2):
    Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines.
    Juan De Los Santos-Jiménez, Tracy Rosales, Bookyung Ko, José A Campos-Sandoval, Francisco J Alonso, Javier Márquez, Ralph J DeBerardinis, José M Matés.
      Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: GLS and GLS2. In glioblastoma, GLS is commonly overexpressed and considered pro-oncogenic. We studied the metabolic effects of inhibiting GLS activity in T98G, LN229, and U87MG human glioblastoma cell lines by using the inhibitor CB-839. We performed metabolomics and isotope tracing experiments using U-13C-labeled Gln, as well as 15N-labeled Gln in the amide group, to determine the metabolic fates of Gln carbon and nitrogen atoms. In the presence of the inhibitor, the results showed an accumulation of Gln and lower levels of tricarboxylic acid cycle intermediates, and aspartate, along with a decreased oxidative labeling and diminished reductive carboxylation-related labeling of these metabolites. Additionally, CB-839 treatment caused decreased levels of metabolites from pyrimidine biosynthesis and an accumulation of intermediate metabolites in the de novo purine nucleotide biosynthesis pathway. The levels of some acetylated and methylated metabolites were significantly increased, including acetyl-carnitine, trimethyl-lysine, and 5-methylcytosine. In conclusion, we analyzed the metabolic landscape caused by the GLS inhibition of CB-839 in human glioma cells, which might lead to the future development of new combination therapies with CB-839.
    Keywords:  CB-839; aspartate; cancer; cancer metabolism; citrate; glioblastoma; glutaminase; glutamine; metabolic reprogramming; metabolomics
    DOI:  https://doi.org/10.3390/cancers15020531
  5. Eur J Neurol. 2023 Jan 16.
    High-dose oral glutamine can reduce CSF glutamate in MELAS without a beneficial clinical or cerebral tissue effect.
    Josef Finsterer, Sounira Mehri.
      
    Keywords:  MELAS; Miller-Fisher syndrome; cerebrospinal fluid; glutamate; glutamine
    DOI:  https://doi.org/10.1111/ene.15682
  6. Ann Transl Med. 2022 Dec;10(24): 1362
    The potential of glutamine metabolism-related long non-coding RNAs (lncRNAs) as prognostic biomarkers in multiple myeloma patients.
    Yun Zhong, Shenghua Xu, Zhe Liu.
       Background: Glutamine (Gln) metabolism has been confirmed as an important fuel in cancer metabolism. This study aimed to uncover potential links of Gln with long non-coding RNAs (lncRNAs) and the prognostic value of Gln-associated lncRNAs in multiple myeloma (MM) patients.
    Methods: The RNA-seq expression profile and corresponding clinical data of gastric cancer obtained from Gene Expression Omnibus (GEO) database. Unsupervised consensus clustering was used to cluster MM samples based on Gln-associated lncRNAs. The overall survival (OS), biological pathways, and immune microenvironment were compared in different subtypes. Differential analysis was utilized to identify differentially expressed lncRNAs (DElncRNAs) in different subtypes. A risk model was constructed based on DElncRNAs by using Cox regression, least absolute shrinkage and selection operator (LASSO), and the stepAIC algorithm.
    Results: We screened 50 Gln-associated lncRNAs and identified 3 molecular subtypes (clust1, clust2, and clust3) based on lncRNA expression profiles. Clust3 subtype showed the worst prognosis and highest enrichment of Gln metabolism pathway. Angiogenesis, epithelial-mesenchymal transition (EMT), and cell cycle-related pathways were relatively activated in clust3. Then, we identified 11 prognostic DElncRNAs for constructing the risk model. The MM samples were divided into high- and low-risk groups with distinct prognosis according to the risk score. The risk score was significantly associated with cell cycle and infiltration of many immune cells.
    Conclusions: This study characterized the role of Gln-associated lncRNAs in Gln metabolism contributing for tumor-related pathways and immune microenvironment in MM patients. The 11 lncRNAs in the risk model may serve as potential targets for exploring the mechanism of Gln metabolism or serve as potential biomarkers for MM prognosis.
    Keywords:  Multiple myeloma (MM); immune microenvironment; long non-coding RNAs (lncRNAs); risk model
    DOI:  https://doi.org/10.21037/atm-22-6190
  7. Breast Cancer Res. 2023 Jan 17. 25(1): 5
    A prospective case-cohort analysis of plasma metabolites and breast cancer risk.
    Victoria L Stevens, Brian D Carter, Eric J Jacobs, Marjorie L McCullough, Lauren R Teras, Ying Wang.
       BACKGROUND: Breast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with breast cancer risk.
    METHODS: Untargeted metabolomic analysis was done on prediagnostic plasma samples from a case-cohort study of 1695 incident breast cancer cases and a 1983 women subcohort drawn from Cancer Prevention Study 3. The associations of 868 named metabolites (per one standard deviation increase) with breast cancer were determined using Prentice-weighted Cox proportional hazards regression modeling.
    RESULTS: A total of 11 metabolites were associated with breast cancer at false discovery rate (FDR) < 0.05 with the majority having inverse association [ranging from RR = 0.85 (95% CI 0.80-0.92) to RR = 0.88 (95% CI 0.82-0.94)] and one having a positive association [RR = 1.14 (95% CI 1.06-1.23)]. An additional 50 metabolites were associated at FDR < 0.20 with inverse associations ranging from RR = 0.88 (95% CI 0.81-0.94) to RR = 0.91 (95% CI 0.85-0.98) and positive associations ranging from RR = 1.13 (95% CI 1.05-1.22) to RR = 1.11 (95% CI 1.02-1.20). Several of these associations validated the findings of previous metabolomic studies. These included findings that several progestogen and androgen steroids were associated with increased risk of breast cancer in postmenopausal women and four phospholipids, and the amino acids glutamine and asparagine were associated with decreased risk of this cancer in pre- and postmenopausal women. Several novel associations were also identified, including a positive association for syringol sulfate, a biomarker for smoked meat, and 3-methylcatechol sulfate and 3-hydroxypyridine glucuronide, which are metabolites of xenobiotics used for the production of pesticides and other products.
    CONCLUSIONS: Our study validated previous metabolite findings and identified novel metabolites associated with breast cancer risk, demonstrating the utility of large metabolomic studies to provide new leads for understanding breast cancer etiology. Our novel findings suggest that consumption of smoked meats and exposure to catechol and pyridine should be investigated as potential risk factors for breast cancer.
    Keywords:  Breast cancer; Metabolites; Metabolomics; Prospective study
    DOI:  https://doi.org/10.1186/s13058-023-01602-x
  8. Trends Cancer. 2023 Jan 14. pii: S2405-8033(22)00268-0. [Epub ahead of print]
    Fasting and fasting mimicking diets in cancer prevention and therapy.
    Olga Blaževitš, Maira Di Tano, Valter D Longo.
      Fasting mimicking diets (FMDs) are emerging as effective dietary interventions with the potential to improve healthspan and decrease the incidence of cancer and other age-related diseases. Unlike chronic dietary restrictions or water-only fasting, FMDs represent safer and less challenging options for cancer patients. FMD cycles increase protection in healthy cells while sensitizing cancer cells to various therapies, partly by generating complex environments that promote differential stress resistance (DSR) and differential stress sensitization (DSS), respectively. More recent data indicate that FMD cycles enhance the efficacy of a range of drugs targeting different cancers in mice by stimulating antitumor immunity. Here, we report on the effects of FMD cycles on cancer prevention and treatment and the mechanisms implicated in these effects.
    Keywords:  cancer treatment; differential stress resistance (DSR); differential stress sensitization (DSS); fasting mimicking diet
    DOI:  https://doi.org/10.1016/j.trecan.2022.12.006
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