bims-glucam 2022-05-29 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–05–29
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells.
Ginsenoside CK induces apoptosis in triple-negative breast cancer cells by targeting glutamine metabolism.
Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury.
Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer.
Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
Targeting Energy Metabolism in Cancer Treatment.
Alloferon Affects the Chemosensitivity of Pancreatic Cancer by Regulating the Expression of SLC6A14.
CD133-Functionalized Gold Nanoparticles as a Carrier Platform for Telaglenastat (CB-839) against Tumor Stem Cells.
Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.
O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.
Developing dietary interventions as therapy for cancer.
Amino acids control blood glucose levels through mTOR signaling.

Metabolites. 2022 May 23. pii: 469. [Epub ahead of print]12(5):

Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells.

Violet A Kiesel, Madeline P Sheeley, Shawn S Donkin, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.

  Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled 13C5-glutamine metabolic tracing, qRT-PCR, measures of reductive-oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells.

Keywords:  ammonium toxicity; breast cancer; glutamine metabolism; metabolic reprogramming; metastasis

DOI:  https://doi.org/10.3390/metabo12050469
Biochem Pharmacol. 2022 May 23. pii: S0006-2952(22)00195-2. [Epub ahead of print] 115101

Ginsenoside CK induces apoptosis in triple-negative breast cancer cells by targeting glutamine metabolism.

Bo Zhang, Rongzhan Fu, Zhiguang Duan, Shihong Shen, Chenhui Zhu, Daidi Fan.

  Breast cancer (BC) has replaced lung cancer as the most common cancer worldwide. Ginsenoside CK (CK) can effectively inhibit triple-negative breast cancer (TNBC), the occurrence and development of which are associated with glutamine addiction. However, the connection between CK and glutamine metabolism in TNBC proliferation and the mechanism of cell death induction remains unclear. Here, we found that high glutamine-addicted TNBC cells were particularly sensitive to CK treatment. CK exerted antitumour activity against TNBC by suppressing glutamine consumption and glutamate production via downregulation of glutaminase 1 (GLS1) expression. CK treatment further decreased cellular ATP production, reduced the utilisation of amino acids associated with glutamine metabolism, and induced glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, consequently triggering apoptosis in TNBC. Furthermore, CK decreased GLS1 expression in SUM159 xenograft mouse mammary tumours and significantly inhibited tumour growth with few side effects. Together, our data provide a powerful theoretical basis for the application of CK as a glutamine metabolic inhibitor in TNBC treatment.

Keywords:  GLS1; Ginsenoside CK; apoptosis; glutamine metabolism; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.bcp.2022.115101
Biomolecules. 2022 May 22. pii: 728. [Epub ahead of print]12(5):

Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury.

Sisi Wang, Xue Li, Qingwen Ma, Qi Wang, Junping Wu, Hongzhi Yu, Kuan Li, Yu Li, Jianhai Wang, Qiuyang Zhang, Youwei Wang, Qi Wu, Huaiyong Chen.

  (1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (p < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (p < 0.05) and metabolome (p < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (p < 0.01) and differentiation (p < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury.

Keywords:  alveolar progenitor cells; glutamine metabolism; idiopathic pulmonary fibrosis; lung regeneration; omics

DOI:  https://doi.org/10.3390/biom12050728
Cancers (Basel). 2022 May 19. pii: 2491. [Epub ahead of print]14(10):

Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer.

Manish Thiruvalluvan, Sandrine Billet, Neil A Bhowmick.

  Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were ineffective in radio-sensitization. However, targeting glutamine bioavailability by L-asparaginase (L-ASP) led to a significant reduction in clonogenicity when combined with irradiation. L-ASP reduced extracellular asparagine and glutamine, but the sensitization effects were driven through its depletion of glutamine. L-ASP led to G2/M cell cycle checkpoint blockade. As evidence, there was a respective delay in DNA repair associated with RAD51 downregulation and upregulation of CHOP, contributing to radiation-induced cell death. A radio-resistant PCa cell line was developed, was found to bypass radiation-induced mitotic catastrophe, and was sensitive to L-ASP/radiation combination treatment. Previously, PCa-associated fibroblasts were reported as a glutamine source supporting tumor progression. As such, glutamine-free media were not effective in promoting radiation-induced PCa cell death when co-cultured with associated primary fibroblasts. However, the administration L-ASP catalyzed glutamine depletion with irradiated co-cultures and catalyzed tumor volume reduction in a mouse model. The clinical history of L-ASP for leukemia patients supports the viability for its repurposing as a radio-sensitizer for PCa patients.

Keywords:  asparaginase; glutamine; prostate cancer; radiation therapy

DOI:  https://doi.org/10.3390/cancers14102491
Gut. 2022 May 27. pii: gutjnl-2021-325117. [Epub ahead of print]

Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.

Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini.

   OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.
DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.
RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.
CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.

Keywords:  AMINO ACIDS; CELL BIOLOGY; LIPID METABOLISM; PANCREATIC CANCER; SIGNAL TRANSDUCTION

DOI:  https://doi.org/10.1136/gutjnl-2021-325117
Int J Mol Sci. 2022 May 16. pii: 5572. [Epub ahead of print]23(10):

Targeting Energy Metabolism in Cancer Treatment.

Joanna Kubik, Ewelina Humeniuk, Grzegorz Adamczuk, Barbara Madej-Czerwonka, Agnieszka Korga-Plewko.

  Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.

Keywords:  cancer metabolism; cancer treatment; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms23105572
Biomedicines. 2022 May 11. pii: 1113. [Epub ahead of print]10(5):

Alloferon Affects the Chemosensitivity of Pancreatic Cancer by Regulating the Expression of SLC6A14.

Hyejung Jo, Dahae Lee, Cheolhyeon Go, Yoojin Jang, Suhyun Bae, Tomoyo Agura, Jiye Hong, Dongmin Kang, Yejin Kim, Jae Seung Kang.

  Pancreatic cancer (PCa), one of the most malignant solid tumors, has a high mortality rate. Although there have been many trials of chemotherapeutic drugs such as gemcitabine, the mortality rates remain significantly higher than for other types of cancer. Therefore, more effective ways of improving conventional therapy for PCa are needed. Cancer cells take up large amounts of glutamine to drive their rapid proliferation. Recent studies show that the amino acid transporter SLC6A14 is upregulated in some cancers alongside glutamine metabolism. Alloferon, a peptide isolated from the insect immune system, exerts anti-viral and anti-inflammatory effects via its immunomodulatory function. In addition, it has anti-tumoral effects, although the underlying mechanisms are largely unknown. Therefore, we investigated the effects of alloferon on the PCa cell lines Panc-1 and AsPC-1. Exposure of these cells to alloferon for 3 weeks led to the downregulation of SLC6A14 expression and decreased glutamine uptake. Given that SLC6A14 plays a role in tumor progression and survival by promoting glutamine uptake into cancer cells, alloferon could be a potential adjuvant for the chemotherapeutic drug gemcitabine.

Keywords:  SLC6A14; alloferon; gemcitabine; glutamine; pancreatic cancer

DOI:  https://doi.org/10.3390/biomedicines10051113
Int J Mol Sci. 2022 May 13. pii: 5479. [Epub ahead of print]23(10):

CD133-Functionalized Gold Nanoparticles as a Carrier Platform for Telaglenastat (CB-839) against Tumor Stem Cells.

Elham Poonaki, Ann-Christin Nickel, Mehdi Shafiee Ardestani, Lars Rademacher, Marilyn Kaul, Evgeny Apartsin, Sven G Meuth, Ali Gorji, Christoph Janiak, Ulf Dietrich Kahlert.

  The failure of a long-lasting curative therapeutic benefit of currently applied chemotherapies against malignant cancers is suggested to be caused by the ineffectiveness of such interventions on cancer stem cells (CSCs). CD133/AC133 is a cell surface protein previously shown to have potential to identify CSCs in various tumors, including brain tumors. Moreover, an increase in the rate of cellular metabolism of glutamine and glucose are contributors to the fast cellular proliferation of some high-grade malignancies. Inhibition of glutaminolysis by utilizing pharmacological inhibitors of the enzyme glutaminase 1 (GLS1) can be an effective anti-CSC strategy. In this study, the clinical-stage GLS1 inhibitor Telaglenastat (CB-839) was loaded into PEGylated gold nanoparticles equipped with the covalently conjugated CD133 aptamer (Au-PEG-CD133-CB-839) and exposed to a collection of CD133-positive brain tumor models in vitro. Our results show that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-postive cancer cells in a dose-dependent manner, which was higher as compared to the effects of treatment of the cells with the individual components of the assembled nanodrug. Interestingly, the treatment effect was observed in glioblastoma stem cells modeling different transcriptomic subtypes of the disease. The presented platform is the fundament for subsequent target specificity characterization and in vivo application.

Keywords:  CD133; cancer stem cells; glutaminase; nanomedicine; onco-metabolism

DOI:  https://doi.org/10.3390/ijms23105479
Mol Metab. 2022 May 19. pii: S2212-8778(22)00085-0. [Epub ahead of print] 101516

Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.

Lilianne Frégeau-Proulx, Aurélie Lacouture, Line Berthiaume, Cindy Weidmann, Mario Harvey, Kevin Gonthier, Jean-François Pelletier, Bertrand Neveu, Cynthia Jobin, Dominic Bastien, Alain Bergeron, Yves Fradet, Louis Lacombe, Isabelle Laverdière, Chantal Atallah, Frédéric Pouliot, Étienne Audet-Walsh.

   OBJECTIVE: The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood.
METHODS: We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis.
RESULTS: First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate-oxaloacetate-citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate-malate conversion.
CONCLUSIONS: Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.

Keywords:  TCA cycle; androgen; fertility; organoids; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2022.101516
Nat Commun. 2022 May 25. 13(1): 2904

O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

Kibum Kim, Hee Chan Yoo, Byung Gyu Kim, Sulhee Kim, Yulseung Sung, Ina Yoon, Ya Chun Yu, Seung Joon Park, Jong Hyun Kim, Kyungjae Myung, Kwang Yeon Hwang, Sunghoon Kim, Jung Min Han.

All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.

DOI: https://doi.org/10.1038/s41467-022-30696-8
Nat Rev Cancer. 2022 May 25.

Developing dietary interventions as therapy for cancer.

Samuel R Taylor, John N Falcone, Lewis C Cantley, Marcus D Goncalves.

Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.

DOI: https://doi.org/10.1038/s41568-022-00485-y
Eur J Cell Biol. 2022 May 19. pii: S0171-9335(22)00043-7. [Epub ahead of print]101(3): 151240

Amino acids control blood glucose levels through mTOR signaling.

Jialin Fan, Ziqiang Yuan, Stephen K Burley, Steven K Libutti, X F Steven Zheng.

  Amino Acids are not only major nutrient sources, but also serve as chemical signals to control cellular growth. Rab1A recently emerged as a key component in amino acid sensing and signaling to activate the mTOR complex1 (mTORC1). In a recently published study [1], we generated tamoxifen-inducible, conditional whole-body Rab1A knockout in adult mice. These mice are viable but develop hyperglycemia and glucose intolerance. Interestingly, Rab1A ablation selectively reduces insulin expression and pancreatic beta-cell population. Mechanistically, branched chain amino acids (BCAA), through the Rab1A-mTORC1 complex, promote the stability and nuclear localization of Pdx1, a master transcription factor that controls growth, function and identity of pancreatic beta-cells. These findings reveal a role and underlying mechanism by which amino acids control body's glucose level through a beta-cell specific function by the Rab1A-mTORC1-Pdx1 signaling axis, which has implications in both diabetes and cancer.

Keywords:  Alpha cell; Amino acid; Beta cell; Cancer; Diabetes; Insulin; Islet; MTOR; Pancreas; Rab1A

DOI:  https://doi.org/10.1016/j.ejcb.2022.151240