bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–12–26
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation.
  2. Amino acid transporters as modulators of glucose homeostasis.
  3. Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.
  4. Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
  5. The Expression of Glutaminases and their Association with Clinicopathological Parameters in the Head and Neck Cancers.
  6. Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.
  7. A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer.
  8. Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation.
  9. High-Throughput Screening Reveals New Glutaminase Inhibitor Molecules.
  10. Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.
  11. Reactivity of γ-glutamyl-cysteine with intracellular and extracellular glutathione metabolic enzymes.
  12. Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells.
  13. Glycolysis under Circadian Control.
  14. Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
  15. Meta-analysis of Glutamine on Immune Function and Post-Operative Complications of Patients With Colorectal Cancer.
  16. Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells.
  17. Cancer metabolism and dietary interventions.
  18. Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme.
  19. Multi-Omic Metabolic Enrichment Network Analysis reveals metabolite-protein physical interaction subnetworks altered in cancer.
  20. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance.
  21. Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
  1. Metab Eng. 2021 Dec 17. pii: S1096-7176(21)00191-9. [Epub ahead of print]69 221-230
    Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation.
    Eleanor H Oates, Maciek R Antoniewicz.
      Adipose tissue plays a major role in regulating lipid and energy homeostasis by storing excess nutrients, releasing energetic substrates through lipolysis, and regulating metabolism of other tissues and organs through endocrine and paracrine signaling. Adipocytes within fat tissues store excess nutrients through increased cell number (hyperplasia), increased cell size (hypertrophy), or both. The differentiation of pre-adipocytes into mature lipid-accumulating adipocytes requires a complex interaction of metabolic pathways that is still incompletely understood. Here, we applied parallel labeling experiments and 13C-metabolic flux analysis to quantify precise metabolic fluxes in proliferating and differentiated 3T3-L1 cells, a widely used model to study adipogenesis. We found that morphological and biomass composition changes in adipocytes were accompanied by significant shifts in metabolic fluxes, encompassing all major metabolic pathways. In contrast to proliferating cells, differentiated adipocytes 1) increased glucose uptake and redirected glucose utilization from lactate production to lipogenesis and energy generation; 2) increased pathway fluxes through glycolysis, oxidative pentose phosphate pathway and citric acid cycle; 3) reduced lactate secretion, resulting in increased ATP generation via oxidative phosphorylation; 4) rewired glutamine metabolism, from glutaminolysis to de novo glutamine synthesis; 5) increased cytosolic NADPH production, driven mostly by increased cytosolic malic enzyme flux; 6) increased production of monounsaturated C16:1; and 7) activated a mitochondrial pyruvate cycle through simultaneous activity of pyruvate carboxylase, malate dehydrogenase and malic enzyme. Taken together, these results quantitatively highlight the complex interplay between pathway fluxes and cell function in adipocytes, and suggest a functional role for metabolic reprogramming in adipose differentiation and lipogenesis.
    Keywords:  3T3-L1 cells; Adipocytes; Adipogensis; Differentiation; Metabolism; de novo lipogenesis
    DOI:  https://doi.org/10.1016/j.ymben.2021.12.005
  2. Trends Endocrinol Metab. 2021 Dec 16. pii: S1043-2760(21)00267-8. [Epub ahead of print]
    Amino acid transporters as modulators of glucose homeostasis.
    Stefan Bröer.
      Amino acids modulate glucose homeostasis. Cytosolic levels of amino acids are regulated by amino acid transporters, modulating insulin release, protein synthesis, cell proliferation, cell fate, and metabolism. In β-cells, amino acid transporters modulate incretin-stimulated insulin release. In the liver, amino acid transporters provide glutamine and alanine for gluconeogenesis. Intestinal amino acid transporters facilitate the intake of amino acids causing protein restriction when inactive. Adipocyte development is regulated by amino acid transporters through activation of mechanistic target of rapamycin (mTORC1) and amino acid-related metabolites. The accumulation and metabolism of branched-chain amino acids (BCAAs) in muscle depends on transporters. The integration between amino acid metabolism and transport is critical for the maintenance and function of tissues and cells involved in glucose homeostasis.
    Keywords:  GCN2; adipocytes; gluconeogenesis; solute carrier; β-cell
    DOI:  https://doi.org/10.1016/j.tem.2021.11.004
  3. Cell Death Discov. 2021 Dec 20. 7(1): 395
    Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.
    Sunsook Hwang, Seungyeon Yang, Minjoong Kim, Youlim Hong, Byungjoo Kim, Eun Kyung Lee, Seung Min Jeong.
      The DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.
    DOI:  https://doi.org/10.1038/s41420-021-00792-7
  4. Biomolecules. 2021 Dec 15. pii: 1888. [Epub ahead of print]11(12):
    Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
    Thi Yen Ly Huynh, Ilona Oscilowska, Jorge Sáiz, Magdalena Nizioł, Weronika Baszanowska, Coral Barbas, Jerzy Palka.
      It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.
    Keywords:  MCF-7crPOX cells; PRODH/POX; glutamine; lactic acid; metformin; proline
    DOI:  https://doi.org/10.3390/biom11121888
  5. Curr Cancer Drug Targets. 2021 Dec 23.
    The Expression of Glutaminases and their Association with Clinicopathological Parameters in the Head and Neck Cancers.
    Haneen A Basheer, Lina Elsalem, Anwar Salem, Artysha Tailor, Keith Hunter, Kamyar Afarinkia.
       BACKGROUND: The increased glutamine metabolism is a characteristic feature of cancer cells. The interconversion between glutamine and glutamate is catalyzed by two glutaminase isoforms, GLS1 and GLS2, which appear to have different roles in different types of cancer. We investigated for the first time the protein expression of GLS1 and GLS2, and their correlation with advanced clinicopathological parameters in head and neck cancers.
    METHOD: Consecutive slides from a tissue microarray comprised of 80 samples ranging from normal to metastatic, were stained immunohistochemically for GLS1, GLS2, HIF-1α or CD147. Following analysis by two expert pathologists we carried out statistical analysis of the scores.
    RESULTS: GLS1 and GLS2 are upregulated at protein level in head and neck tumours compared to normal tissues and this increased expression correlated positively (GLS1) and negatively (GLS2) with tumor grade, indicating a shift of expression between GLS enzyme isoforms based on tumor differentiation. Increased expression of GLS1 was associated with high CD147 expression; and elevated GLS2 expression was associated with both high CD147 and high HIF-1α expressions. The correlation of the GLS1 and GLS2 with HIF-1α or CD147 was strongly associated with more advanced clinicopathological parameters.
    CONCLUSION: The increased expression of GLS1 and GLS2 may be explored as a new treatment for head and neck cancers.
    Keywords:  CD147; GLS1; GLS2; Glutaminases; Head and neck cancers.; Immunohistochemistry
    DOI:  https://doi.org/10.2174/1568009622666211224111425
  6. Biomedicines. 2021 Dec 18. pii: 1942. [Epub ahead of print]9(12):
    Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.
    Elisabetta Iessi, Rosa Vona, Camilla Cittadini, Paola Matarrese.
      In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.
    Keywords:  OXPHOS; acidity; anticancer therapy; cancer cell metabolism; cell death; chemoresistance; glucose; glycolysis; oxidative metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines9121942
  7. Biomolecules. 2021 Nov 23. pii: 1749. [Epub ahead of print]11(12):
    A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer.
    Jing-Jing Wang, Michelle Kwan-Yee Siu, Yu-Xin Jiang, Thomas Ho-Yin Leung, David Wai Chan, Huo-Gang Wang, Hextan Yuen-Sheung Ngan, Karen Kar-Loen Chan.
      Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan-Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.
    Keywords:  T cells; glutamine metabolism; immunotherapy; ovarian cancer
    DOI:  https://doi.org/10.3390/biom11121749
  8. EMBO J. 2021 Dec 20. e110306
    Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation.
    Jialiang Shao, Tiezhu Shi, Hua Yu, Yufeng Ding, Liping Li, Xiang Wang, Xiongjun Wang.
      
    DOI:  https://doi.org/10.15252/embj.2021110306
  9. ACS Pharmacol Transl Sci. 2021 Dec 10. 4(6): 1849-1866
    High-Throughput Screening Reveals New Glutaminase Inhibitor Molecules.
    Renna K E Costa, Camila T Rodrigues, Jean C H Campos, Luciana S Paradela, Marilia M Dias, Bianca Novaes da Silva, Cyro von Zuben de Valega Negrao, Kaliandra de Almeida Gonçalves, Carolline F R Ascenção, Douglas Adamoski, Gustavo Fernando Mercaldi, Alliny C S Bastos, Fernanda A H Batista, Ana Carolina Figueira, Artur T Cordeiro, Andre L B Ambrosio, Rafael V C Guido, Sandra M G Dias.
      The glutaminase (GLS) enzyme hydrolyzes glutamine into glutamate, an important anaplerotic source for the tricarboxylic acid cycle in rapidly growing cancer cells under the Warburg effect. Glutamine-derived α-ketoglutarate is also an important cofactor of chromatin-modifying enzymes, and through epigenetic changes, it keeps cancer cells in an undifferentiated state. Moreover, glutamate is an important neurotransmitter, and deregulated glutaminase activity in the nervous system underlies several neurological disorders. Given the proven importance of glutaminase for critical diseases, we describe the development of a new coupled enzyme-based fluorescent glutaminase activity assay formatted for 384-well plates for high-throughput screening (HTS) of glutaminase inhibitors. We applied the new methodology to screen a ∼30,000-compound library to search for GLS inhibitors. The HTS assay identified 11 glutaminase inhibitors as hits that were characterized by in silico, biochemical, and glutaminase-based cellular assays. A structure-activity relationship study on the most promising hit (C9) allowed the discovery of a derivative, C9.22, with enhanced in vitro and cellular glutaminase-inhibiting activity. In summary, we discovered a new glutaminase inhibitor with an innovative structural scaffold and described the molecular determinants of its activity.
    DOI:  https://doi.org/10.1021/acsptsci.1c00226
  10. Biology (Basel). 2021 Dec 03. pii: 1267. [Epub ahead of print]10(12):
    Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.
    Consuelo Ripoll, Mar Roldan, Maria J Ruedas-Rama, Angel Orte, Miguel Martin.
      Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called 'metabophenotypes', in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.
    Keywords:  breast cancer; metabolic profiling; metabolic reprogramming; tumor metabolism
    DOI:  https://doi.org/10.3390/biology10121267
  11. FEBS Lett. 2021 Dec 18.
    Reactivity of γ-glutamyl-cysteine with intracellular and extracellular glutathione metabolic enzymes.
    Misa Muraoka, Saki Yoshida, Moeka Ohno, Hideyuki Matsuura, Kazuya Nagano, Yoshihiko Hirata, Masayoshi Arai, Kazumasa Hirata.
      Gamma-glutamyl-cysteine (γ-EC) is a precursor of glutathione (GSH) biosynthesis. We investigated whether it functions as a substrate for three intracellular and one extracellular GSH metabolic enzymes, which mediate the antioxidant defense function of GSH. Among them, glutathione peroxidase, glutathione S-transferase, and γ-glutamyl transferase (GGT) exhibited substrate specificity for γ-EC, whereas glutathione reductase did not. The specificities of γ-EC and its disulfide form to GGT were comparable to GSH and its oxidized form, GSSG, respectively. These result indicate that they can supply GSH constituent amino acids, glutamate, cysteine, and cystine through degradation by GGT. γ-EC may contribute valuable antioxidant defense properties as a food and cosmetic additive.
    Keywords:  Glutathione; antioxidant defense; gamma-glutamyl-cysteine; glutathione metabolic enzyme
    DOI:  https://doi.org/10.1002/1873-3468.14261
  12. Bioengineering (Basel). 2021 Dec 10. pii: 208. [Epub ahead of print]8(12):
    Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells.
    Thora Bjorg Sigmarsdottir, Sarah McGarrity, Adrián López García de Lomana, Aristotelis Kotronoulas, Snaevar Sigurdsson, James T Yurkovich, Ottar Rolfsson, Olafur Eysteinn Sigurjonsson.
      Mesenchymal stromal cells (MSCs) are multipotent post-natal stem cells with applications in tissue engineering and regenerative medicine. MSCs can differentiate into osteoblasts, chondrocytes, or adipocytes, with functional differences in cells during osteogenesis accompanied by metabolic changes. The temporal dynamics of these metabolic shifts have not yet been fully characterized and are suspected to be important for therapeutic applications such as osteogenesis optimization. Here, our goal was to characterize the metabolic shifts that occur during osteogenesis. We profiled five key extracellular metabolites longitudinally (glucose, lactate, glutamine, glutamate, and ammonia) from MSCs from four donors to classify osteogenic differentiation into three metabolic stages, defined by changes in the uptake and secretion rates of the metabolites in cell culture media. We used a combination of untargeted metabolomic analysis, targeted analysis of 13C-glucose labelled intracellular data, and RNA-sequencing data to reconstruct a gene regulatory network and further characterize cellular metabolism. The metabolic stages identified in this proof-of-concept study provide a framework for more detailed investigations aimed at identifying biomarkers of osteogenic differentiation and small molecule interventions to optimize MSC differentiation for clinical applications.
    Keywords:  gene regulatory network; glycolysis; mesenchymal stromal cells (MSCs); metabolic changes; metabolism; metabolites; osteogenic differentiation; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/bioengineering8120208
  13. Int J Mol Sci. 2021 Dec 20. pii: 13666. [Epub ahead of print]22(24):
    Glycolysis under Circadian Control.
    Jana Zlacká, Michal Zeman.
      Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.
    Keywords:  circadian; clock genes; glycolysis; metabolic reprogramming; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms222413666
  14. Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10
    Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
    Dylan Gerard Ryan, Ming Yang, Hiran A Prag, Giovanny Rodriguez Blanco, Efterpi Nikitopoulou, Marc Segarra-Mondejar, Christopher A Powell, Tim Young, Nils Burger, Jan Lj Miljkovic, Michal Minczuk, Michael P Murphy, Alex von Kriegsheim, Christian Frezza.
      The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.
    Keywords:  biochemistry; cell biology; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.72593
  15. Front Nutr. 2021 ;8 765809
    Meta-analysis of Glutamine on Immune Function and Post-Operative Complications of Patients With Colorectal Cancer.
    Tao Yang, Xuhong Yan, Yibo Cao, Tiantian Bao, Guangsong Li, Shengliang Gu, Kai Xiong, Tianbao Xiao.
      The aim of this meta-analysis was to evaluate the clinical significance of glutamine in the management of patients with colorectal cancer (CRC) after radical operation. Electronic databases, including PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), VIP medicine information system (VIP), and Wanfang electronic databases were comprehensively searched from inception to 30, July 2021. Prospective randomized trials with glutamine vs. routine nutrition or blank therapy were selected. The immune function related indicators (including IgA, IgG, IgM, CD4+, CD8+, and the ratio of CD4+/CD8+), post-operative complications [including surgical site infection (SSI), anastomotic leakage, and length of hospital stay (LOS)], and corresponding 95% confidence intervals (CIs) were assessed in the pooled analysis. Subsequently, the heterogeneity between studies, sensitivity, publication bias, and meta-regression analysis were performed. Consequently, 31 studies which contained 2,201 patients (1,108 in the glutamine group and 1,093 in the control group) were included. Results of pooled analysis indicated that glutamine significantly improved the humoral immune function indicators [including IgA (SMD = 1.15, 95% CI: 0.72-1.58), IgM (SMD = 0.68, 95% CI: 0.48-0.89), and IgG (SMD = 1.10, 95% CI: 0.70-1.50)], and the T cell immune function indicators [including CD4+ (SMD = 0.76, 95% CI: 0.53-0.99) and the ratio of CD4+/CD8+ (SMD = 0.92, 95% CI: 0.57-1.28)]. Meanwhile, the content of CD8+ was decreased significantly (SMD = -0.50, 95% CI: -0.91 to -0.10) followed by glutamine intervention. Pooled analysis of SSI (RR = 0.48, 95% CI: 0.30-0.75), anastomotic leakage (RR = 0.23, 95% CI: 0.09-0.61), and LOS (SMD = -1.13, 95% CI: -1.68 to -0.58) were decreased significantly in glutamine group compared with control group. Metaregression analysis revealed that the covariate of small-sample effects influenced the robustness and reliability of IgG outcome potentially. Findings of the present work demonstrated that glutamine ought to be applied as an effective immunenutrition therapy in the treatment of patients with CRC after radical surgery. The present meta-analysis has been registered in PROSPERO (no. CRD42021243327). Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, Identifier: CRD42021243327.
    Keywords:  T cell immunity; colorectal cancer; humoral immunity; meta-analysis; post-operative complications
    DOI:  https://doi.org/10.3389/fnut.2021.765809
  16. Biomedicines. 2021 Dec 16. pii: 1927. [Epub ahead of print]9(12):
    Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells.
    Ji Hee Ha, Muralidharan Jayaraman, Revathy Nadhan, Srishti Kashyap, Priyabrata Mukherjee, Ciro Isidoro, Yong Sang Song, Danny N Dhanasekaran.
      Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy.
    Keywords:  5-HT; GABA; glutamate; metabolomics; oncometabolite; ovarian cancer
    DOI:  https://doi.org/10.3390/biomedicines9121927
  17. Cancer Biol Med. 2021 Dec 22. pii: j.issn.2095-3941.2021.0461. [Epub ahead of print]
    Cancer metabolism and dietary interventions.
    Lin Qian, Fan Zhang, Miao Yin, Qunying Lei.
      Metabolic remodeling is a key feature of cancer development. Knowledge of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells, the so-called Warburg effect. Malignant cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal cells. Thus, targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical practice. In particular, the management of nutrient availability is becoming more attractive in cancer treatment. In this review, we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor metabolism. First, we present a comprehensive overview of changes in macronutrient metabolism. Carbohydrates, amino acids, and lipids, are rewired in the cancer microenvironment individually or systematically. Second, we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.
    Keywords:  Cancer metabolism; amino acid; carbohydrate; diet intervention; lipid
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0461
  18. Cancers (Basel). 2021 Dec 07. pii: 6169. [Epub ahead of print]13(24):
    Transcriptional Regulation of Amino Acid Transport in Glioblastoma Multiforme.
    Robyn A Umans, Joelle Martin, Megan E Harrigan, Dipan C Patel, Lata Chaunsali, Aarash Roshandel, Kavya Iyer, Michael D Powell, Ken Oestreich, Harald Sontheimer.
      Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1Met, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.
    Keywords:  SLC7A11; glioblastoma multiforme; glutamate; p53
    DOI:  https://doi.org/10.3390/cancers13246169
  19. Mol Cell Proteomics. 2021 Dec 18. pii: S1535-9476(21)00161-4. [Epub ahead of print] 100189
    Multi-Omic Metabolic Enrichment Network Analysis reveals metabolite-protein physical interaction subnetworks altered in cancer.
    Benjamin C Blum, Weiwei Lin, Matthew L Lawton, Qian Liu, Julian Kwan, Isabella Turcinovic, Ryan Hekman, Pingzhao Hu, Andrew Emili.
      Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce MOMENTA, an integrative multi-omic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.
    Keywords:  Cancer; Multi-omic; Networks; Proteomics; Systems Biology
    DOI:  https://doi.org/10.1016/j.mcpro.2021.100189
  20. Cancer Cell. 2021 Dec 14. pii: S1535-6108(21)00613-9. [Epub ahead of print]
    Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance.
    Hannah N Bell, Ryan J Rebernick, Joshua Goyert, Rashi Singhal, Miljan Kuljanin, Samuel A Kerk, Wesley Huang, Nupur K Das, Anthony Andren, Sumeet Solanki, Shannon L Miller, Peter K Todd, Eric R Fearon, Costas A Lyssiotis, Steven P Gygi, Joseph D Mancias, Yatrik M Shah.
      Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
    Keywords:  Lactobacillus reuteri; Microbiome; Reuterin; colorectal cancer; metabolites; protein oxidation
    DOI:  https://doi.org/10.1016/j.ccell.2021.12.001
  21. Int J Mol Sci. 2021 Dec 14. pii: 13435. [Epub ahead of print]22(24):
    Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
    Chia-Lin Chen, Ching-Yu Lin, Hsing-Jien Kung.
      Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.
    Keywords:  OXPHOS; cancer therapy; mitochondria
    DOI:  https://doi.org/10.3390/ijms222413435
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