bims-glucam 2022-08-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–08–21
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Elucidation of an mTORC2-PKC-NRF2 pathway that sustains the ATF4 stress response and identification of Sirt5 as a key ATF4 effector.
Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
[18F]-(2S,4R)4-Fluoroglutamine PET Imaging of Glutamine Metabolism in Murine Models of Hepatocellular Carcinoma (HCC).
Glucose feeds the tricarboxylic acid cycle via excreted ethanol in fermenting yeast.
The impact of metabolic supply lines - and the patterns between them - on the development of distant metastases in 64 women with breast cancer.
Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.
Integrative analysis of plasma metabolomics and proteomics reveals the metabolic landscape of breast cancer.
Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.
Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors.
Bioinformatic analysis of the role of solute carrier-glutamine transporters in breast cancer.
Evaluation of Glutamine Utilization in Patients With Sickle Cell Disease.

Cell Death Discov. 2022 Aug 13. 8(1): 357

Elucidation of an mTORC2-PKC-NRF2 pathway that sustains the ATF4 stress response and identification of Sirt5 as a key ATF4 effector.

Ruizhi Li, Kristin F Wilson, Richard A Cerione.

Proliferating cancer cells are dependent on glutamine metabolism for survival when challenged with oxidative stresses caused by reactive oxygen species, hypoxia, nutrient deprivation and matrix detachment. ATF4, a key stress responsive transcription factor, is essential for cancer cells to sustain glutamine metabolism when challenged with these various types of stress. While it is well documented how the ATF4 transcript is translated into protein as a stress response, an important question concerns how the ATF4 message levels are sustained to enable cancer cells to survive the challenges of nutrient deprivation and damaging reactive oxygen species. Here, we now identify the pathway in triple negative breast cancer cells that provides a sustained ATF4 response and enables their survival when encountering these challenges. This signaling pathway starts with mTORC2, which upon sensing cellular stresses arising from glutamine deprivation or an acute inhibition of glutamine metabolism, initiates a cascade of events that triggers an increase in ATF4 transcription. Surprisingly, this signaling pathway is not dependent on AKT activation, but rather requires the mTORC2 target, PKC, which activates the transcription factor Nrf2 that then induces ATF4 expression. Additionally, we identify a sirtuin family member, the NAD+-dependent de-succinylase Sirt5, as a key transcriptional target for ATF4 that promotes cancer cell survival during metabolic stress. Sirt5 plays fundamental roles in supporting cancer cell metabolism by regulating various enzymatic activities and by protecting an enzyme essential for glutaminolysis, glutaminase C (GAC), from degradation. We demonstrate that ectopic expression of Sirt5 compensates for knockdowns of ATF4 in cells exposed to glutamine deprivation-induced stress. These findings provide important new insights into the signaling cues that lead to sustained ATF4 expression as a general stress-induced regulator of glutamine metabolism, as well as highlight Sirt5 an essential effector of the ATF4 response to metabolic stress.

DOI: https://doi.org/10.1038/s41420-022-01156-5
Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01015-4. [Epub ahead of print]40(7): 111198

Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.

Mahmud O Abdullah, Run X Zeng, Chelsea L Margerum, David Papadopoli, Cian Monnin, Kaylee B Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J W Rattray, Sheela A Abraham, Eeva-Liisa Eskelinen, David G Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y W Chan.

  The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.

Keywords:  CP: Cell biology; CP: Metabolism; Drp1; Mfn1; Mfn2; Opa1; amino acid sensing; arginine; dynamics; fusion; glutamine; hyperfusion; leucine; mitochondria; stable isotope tracer

DOI:  https://doi.org/10.1016/j.celrep.2022.111198
Mol Imaging. 2022 ;2022 5185951

[18F]-(2S,4R)4-Fluoroglutamine PET Imaging of Glutamine Metabolism in Murine Models of Hepatocellular Carcinoma (HCC).

Youngho Seo, Miranda C Craig, Stephanie T Murphy, Jinjin Feng, Xin Chen, Mariia Yuneva.

Purpose: Quantitative in vivo [18F]-(2S,4R)4-fluoroglutamine ([18F]4-FGln or more simply [18F]FGln) metabolic kinetic parameters are compared with activity levels of glutamine metabolism in different types of hepatocellular carcinoma (HCC).
Methods: For this study, we used two transgenic mouse models of HCC induced by protooncogenes, MYC, and MET. Biochemical data have shown that tumors induced by MYC have increased levels of glutamine metabolism compared to those induced by MET. One-hour dynamic [18F]FGln PET data were acquired and reconstructed for fasted MYC mice (n = 11 tumors from 7 animals), fasted MET mice (n = 8 tumors from 6 animals), fasted FVBN controls (n = 8 normal liver regions from 6 animals), nonfasted MYC mice (n = 16 tumors from 6 animals), and nonfasted FVBN controls (n = 8 normal liver regions from 3 animals). The influx rate constants (K 1) using the one-tissue compartment model were derived for each tumor with the left ventricular blood pool input function.
Results: Influx rate constants were significantly higher for MYC tumors (K 1 = 0.374 ± 0.133) than for MET tumors (K 1 = 0.141 ± 0.058) under fasting conditions (P = 0.0002). Rate constants were also significantly lower for MET tumors (K 1 = 0.141 ± 0.135) than normal livers (K 1 = 0.332 ± 0.179) under fasting conditions (P = 0.0123). Fasting conditions tested for MYC tumors and normal livers did not result in any significant difference with P values > 0.005.
Conclusion: Higher influx rate constants corresponded to elevated levels of glutamine metabolism as determined by biochemical assays. The data showed that there is a distinctive difference in glutamine metabolism between MYC and MET tumors. Our study has demonstrated the potential of [18F]FGln PET imaging as a tool to assess glutamine metabolism in HCC tumors in vivo with a caution that it may not be able to clearly distinguish HCC tumors from normal liver tissue.

DOI: https://doi.org/10.1155/2022/5185951
Nat Chem Biol. 2022 Aug 15.

Glucose feeds the tricarboxylic acid cycle via excreted ethanol in fermenting yeast.

Tianxia Xiao, Artem Khan, Yihui Shen, Li Chen, Joshua D Rabinowitz.

Ethanol and lactate are typical waste products of glucose fermentation. In mammals, glucose is catabolized by glycolysis into circulating lactate, which is broadly used throughout the body as a carbohydrate fuel. Individual cells can both uptake and excrete lactate, uncoupling glycolysis from glucose oxidation. Here we show that similar uncoupling occurs in budding yeast batch cultures of Saccharomyces cerevisiae and Issatchenkia orientalis. Even in fermenting S. cerevisiae that is net releasing ethanol, media 13C-ethanol rapidly enters and is oxidized to acetaldehyde and acetyl-CoA. This is evident in exogenous ethanol being a major source of both cytosolic and mitochondrial acetyl units. 2H-tracing reveals that ethanol is also a major source of both NADH and NADPH high-energy electrons, and this role is augmented under oxidative stress conditions. Thus, uncoupling of glycolysis from the oxidation of glucose-derived carbon via rapidly reversible reactions is a conserved feature of eukaryotic metabolism.

DOI: https://doi.org/10.1038/s41589-022-01091-7
Oncol Lett. 2022 Sep;24(3): 327

The impact of metabolic supply lines - and the patterns between them - on the development of distant metastases in 64 women with breast cancer.

Oliver Abrahamsen, Eva Balslev, Mette Christensen, Flemming Wibrand, Esben Budtz-Jørgensen, Estrid Høgdall.

  Cancer cells upregulate their metabolism to underlie the increased malignant activity. This requires an increased amount of 'metabolic building materials', for example glucose, amino acids etc., which have the blood circulation as their principal supply lines. Targeting these metabolic supply lines, and thus the availability of metabolic building materials in the blood, therefore carries treatment potential. A central observation is that the malignant alterations comprise great complexity and that compensatory mechanisms exist. Therefore, targeted supply lines should presumably constitute specific patterns to achieve therapeutic effect. The aim of the present study was to investigate if such patterns could be seen to correlate with the development of distant metastases. The study was conducted using a case-cohort design. In total, 64 women diagnosed with breast cancer between January 2011 and December 2015 were included. Among these, 32 had developed distant metastases and 32 had not. From a blood sample drawn at the time of diagnosis, the levels of glucose (HbA1c), glutamine, arginine and cystathionine were measured. Cox regression was applied to investigate the impact of the supply lines of these 'building materials' and specifically the patterns between them on the development of distant metastases. The results demonstrate a significant impact of the investigated metabolic supply lines, centrally in relation to interaction between them and in relation to the impact of the increased cumulated utilization of multiple supply lines simultaneously. In conclusion, the results indicated that the metabolic supply lines may impact clinical outcome, and, in this regard, the results placed a substantial emphasis on the effect of the patterns between these supply lines.

Keywords:  amino acids; cancer metabolism; clinical outcome; glucose; metastasis

DOI:  https://doi.org/10.3892/ol.2022.13447
Nat Cancer. 2022 Aug 18.

Cancer-associated fibroblasts employ NUFIP1-dependent autophagy to secrete nucleosides and support pancreatic tumor growth.

Meng Yuan, Bo Tu, Hengchao Li, Huanhuan Pang, Nan Zhang, Minghe Fan, Jingru Bai, Wei Wang, Zhaoqi Shu, Christopher C DuFort, Sihan Huo, Jie Zhai, Ke Yao, Lina Wang, Haoqiang Ying, Wei-Guo Zhu, Deliang Fu, Zeping Hu, Ying Zhao.

Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.

DOI: https://doi.org/10.1038/s43018-022-00426-6
Cancer Metab. 2022 Aug 17. 10(1): 13

Integrative analysis of plasma metabolomics and proteomics reveals the metabolic landscape of breast cancer.

Rui An, Haitao Yu, Yanzhong Wang, Jie Lu, Yuzhen Gao, Xinyou Xie, Jun Zhang.

   BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer. Currently, mammography and breast ultrasonography are the main clinical screening methods for BC. Our study aimed to reveal the specific metabolic profiles of BC patients and explore the specific metabolic signatures in human plasma for BC diagnosis.
METHODS: This study enrolled 216 participants, including BC patients, benign patients, and healthy controls (HC) and formed two cohorts, one training cohort and one testing cohort. Plasma samples were collected from each participant and subjected to perform nontargeted metabolomics and proteomics. The metabolic signatures for BC diagnosis were identified through machine learning.
RESULTS: Metabolomics analysis revealed that BC patients showed a significant change of metabolic profiles compared to HC individuals. The alanine, aspartate and glutamate pathways, glutamine and glutamate metabolic pathways, and arginine biosynthesis pathways were the critical biological metabolic pathways in BC. Proteomics identified 29 upregulated and 2 downregulated proteins in BC. Our integrative analysis found that aspartate aminotransferase (GOT1), L-lactate dehydrogenase B chain (LDHB), glutathione synthetase (GSS), and glutathione peroxidase 3 (GPX3) were closely involved in these metabolic pathways. Support vector machine (SVM) demonstrated a predictive model with 47 metabolites, and this model achieved a high accuracy in BC prediction (AUC = 1). Besides, this panel of metabolites also showed a fairly high predictive power in the testing cohort between BC vs HC (AUC = 0.794), and benign vs HC (AUC = 0.879).
CONCLUSIONS: This study uncovered specific changes in the metabolic and proteomic profiling of breast cancer patients and identified a panel of 47 plasma metabolites, including sphingomyelins, glutamate, and cysteine could be potential diagnostic biomarkers for breast cancer.

Keywords:  Breast neoplasms; Machine learning; Metabolomics; Plasma; Proteomics

DOI:  https://doi.org/10.1186/s40170-022-00289-6
Prostate. 2022 Aug 18.

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.

Mikolaj J Filon, Amani A Gillette, Bing Yang, Tariq A Khemees, Melissa C Skala, David F Jarrard.

   BACKGROUND: Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment.
METHODS: A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145.
RESULTS: Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration.
CONCLUSIONS: Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.

Keywords:  androgen deprivation therapy; mass spectrometry; metabolism; optical metabolic imaging; prostate cancer

DOI:  https://doi.org/10.1002/pros.24428
Theranostics. 2022 ;12(13): 6038-6056

Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors.

Shuting Cao, Yu-Wen Hung, Yi-Chang Wang, Yiyin Chung, Yue Qi, Ching Ouyang, Xiancai Zhong, Weidong Hu, Alaysia Coblentz, Ellie Maghami, Zuoming Sun, H Helen Lin, David K Ann.

  Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity. Methods: A syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion. Results: We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice. Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.

Keywords:  CD8; Treg; autophagy; glutamine; tumor microenvironment

DOI:  https://doi.org/10.7150/thno.73896
Ann Transl Med. 2022 Jul;10(14): 777

Bioinformatic analysis of the role of solute carrier-glutamine transporters in breast cancer.

Xin Zhao, Liang Jin, Yujie Liu, Zhenzhen Liu, Qiang Liu.

   Background: Breast cancer (BC) is a highly heterogeneous disease. Solute carriers (SLCs) have been involved in the tumor progression of various cancer types. This study aimed to evaluate the role of these SLC-related glutamine transporters in the prognosis of BC patients by bioinformatics analysis.
Methods: This study examined the transcription and prognostic data for glutamine-related transporters in BC from Oncomine Database, which is currently the largest oncogene microarray database platform in the world. As well as Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier (K-M), and cBioPortal online resources. The Tumor Immune Estimation Resource (TIMER) and GEPIA were also used to examine the relationship between SLCs and immune cell infiltration.
Results: The expression levels of SLC1A5, SLC3A2, SLC7A5, SLC7A8, and SLC38A1 were higher in BC tissues than normal breast tissues, but the expression level of SLC6A14 was lower. The expression levels of SLC7A5, SLC7A8, SLC6A14, and SLC38A2 were related to a later clinical tumor stage. In the K-M analyses, The K-M curves revealed that patients with high SLC1A5 expression had a poor prognosis (OS HR =1.28, 95% CI: 1.06-1.54; P=0.01). The high expression of SLC3A2 was significantly correlated with a poor prognosis (DMFS HR =1.19, 95% CI: 1.02-1.39; P=0.027). Increased SLC7A5 mRNA levels and decreased SLC7A8 mRNA levels were significantly associated with a poor prognosis in terms of OS, RFS, DMFS and PPS. The high expression of SLC6A14 was significantly correlated with a poor prognosis (PPS HR =1.35, 95% CI: 1.07-1.7; P=0.011). The high expression of SLC38A1 was correlated with a better prognosis than low expression of SLC38A1 (RFS HR =0.84, 95% CI: 0.76-0.93; P=0.00077; DMFS HR =0.78, 95% CI: 0.67-0.91; P=0.0013). The infiltration of immune cells and their marker genes were associated with SLC1A5, SLC3A2, SLC7A5, SLC7A8, SLC6A14, SLC38A1, and SLC38A2 expression. SLC7A5, SLC7A8, SLC38A1, and SLC38A2 have the potential to regulate polarization in tumor-associated macrophages.
Conclusions: SLC7A5, SLC7A8, SLC38A1, and SLC38A2 may regulate the polarization of tumor-associated macrophages (TAMs). SLC1A5, SLC3A2, SLC7A5, and SLC6A14 may be promising biomarkers for the BC diagnosis and may represent potential therapeutic targets for these patients.

Keywords:  Solute carrier (SLC); bioinformatics; breast cancer (BC); prognosis; tumor-immune infiltration

DOI:  https://doi.org/10.21037/atm-22-2620
J Pediatr Hematol Oncol. 2022 Aug 08.

Evaluation of Glutamine Utilization in Patients With Sickle Cell Disease.

Han-Wei Wu, Michael Gannon, Lewis L Hsu.

Glutamine (Gln) was FDA-approved in 2017 to reduce acute sickle cell disease (SCD) pain and acute chest syndrome. However, typical pediatric patients with SCD exhibit moderate adherence, measured by a medication possession ratio <80%. This study examined Gln utilization in a "real-world" clinical setting to determine factors influencing medication adherence and to characterize the impact of an interdisciplinary team approach at an institution with specialty pharmacy services. A retrospective chart review identified 40 patients prescribed Gln by sickle cell specialists over a 2-year period and met selection criteria. Gln medication possession ratio for pediatric (72%) and adult (76%) patients were higher than other SCD medications. Pediatric patients (74%) demonstrated significantly lower first-attempt insurance approval rate compared with adult patients (95%) (P=0.0026), suggesting an initial access barrier for pediatric patients. Pediatric patients demonstrated significantly higher number of medication fills (9.11 fills) compared with adult patients (3.86 fills) (P=0.007), which suggests interdisciplinary collaboration may facilitate sustainable management of a new therapy. The majority of pediatric (89%) and adult (90%) patients reported high satisfaction with Gln ("excellent") with minor or no side effects. Multidisciplinary health care provider collaborations and tracking medication adherence metrics can help address barriers to care for SCD patients.

DOI: https://doi.org/10.1097/MPH.0000000000002519