bims-glucam 2022-06-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒06‒26
seventeen papers selected by
Sreeparna Banerjee
Middle East Technical University

Loss of Heterozygosity for KrasG12D Promotes Malignant Phenotype of Pancreatic Ductal Adenocarcinoma by Activating HIF-2α-c-Myc-Regulated Glutamine Metabolism.
PET/MR Imaging of a Lung Metastasis Model of Clear Cell Renal Cell Carcinoma with (2S,4R)-4-[18F]Fluoroglutamine.
Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review).
Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells.
Silybin suppresses ovarian cancer cell proliferation by inhibiting isocitrate dehydrogenase 1 activity.
Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells.
α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting.
Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes.
Metabolic Profiling of Bladder Cancer Patients' Serum Reveals Their Sensitivity to Neoadjuvant Chemotherapy.
Balancing nutrient and energy demand and supply via autophagy.
Targeting mitochondrial metabolism for metastatic cancer therapy.
Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers.
Targeting autophagy as a therapeutic strategy against pancreatic cancer.
Inhibition of glutathione metabolism can limit the development of pancreatic cancer.
Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches.
A pipeline for the reconstruction and evaluation of context-specific human metabolic models at a large-scale.
On the evolutionary history of the twenty encoded amino acids.

Int J Mol Sci. 2022 Jun 15. pii: 6697. [Epub ahead of print]23(12):

Loss of Heterozygosity for KrasG12D Promotes Malignant Phenotype of Pancreatic Ductal Adenocarcinoma by Activating HIF-2α-c-Myc-Regulated Glutamine Metabolism.

Yu Ma, Sunkai Ling, Yuan Li, Mingyue Hu, Bo Kong, Peilin Huang, Hui Liu.

  Loss of heterozygosity (LOH) for KRAS, in which a wild-type KRAS allele is progressively lost, promotes invasive and migratory abilities of pancreatic ductal adenocarcinoma (PDAC) cells and tissues. Moreover, the occurrence of KrasG12D-LOH activates nonclassical glutamine metabolism, which is related to the malignant behavior of PDAC cells. Herein, we aim to demonstrate the regulatory link between hypoxia-inducible factor-2α (HIF-2α) and glutamine metabolism that mediates malignant phenotypes in KrasG12D-LOH PDAC cells. HIF-2α-shRNA knockdown lentivirus transfection and metabolite analysis were performed in KrasG12D-LOH and KrasG12D cell lines, respectively. Cell proliferation, migration, and invasion were examined using Cell Counting Kit-8, colony formation, and Transwell assays. Cell cycle phase and apoptosis were determined using flow cytometry. Western blotting and real-time quantitative PCR were also performed. Additionally, a subcutaneous xenograft mouse model was established. LOH stimulated HIF-2α activity and transactivated c-Myc, which has a central regulatory effect on glutamine metabolism independent of hypoxia. Meanwhile, HIF-2α silencing repressed KrasG12D-LOH PDAC cell proliferation, invasion, and migration. HIF-2α knockdown inhibited glutamine uptake and GOT1 expression via a c-Myc-dependent pathway. Collectively, KrasG12D-LOH can activate HIF-2α to regulate c-Myc-mediated glutamine metabolism and promote malignant phenotypes. Moreover, targeting HIF-2α-c-Myc regulated nonclassical glutamine metabolism, providing a new therapeutic perspective for KrasG12D-LOH PDAC.

Keywords:  HIF-2α; KrasG12D; c-Myc; glutamine metabolism; loss of heterozygosity

DOI:  https://doi.org/10.3390/ijms23126697
Mol Imaging Biol. 2022 Jun 22.

PET/MR Imaging of a Lung Metastasis Model of Clear Cell Renal Cell Carcinoma with (2S,4R)-4-[18F]Fluoroglutamine.

Alyssa C Pollard, Vincenzo Paolillo, Bhasker Radaram, Sarah Qureshy, Li Li, Tapati Maity, Lei Wang, Md Nasir Uddin, Christopher G Wood, Jose A Karam, Mark D Pagel, David Piwnica-Worms, Steven W Millward, Natalie Wall Fowlkes, William Norton, Brian J Engel, Federica Pisaneschi, Niki M Zacharias.

  PURPOSE: Metabolic reprogramming plays an important role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Currently, positron emission tomography (PET) reporters are not used clinically to visualize altered glutamine metabolism in ccRCC, which greatly hinders detection, staging, and real-time therapeutic assessment. We sought to determine if (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) could be used to interrogate altered glutamine metabolism in ccRCC lesions in the lung.PROCEDURES: We generated a novel ccRCC lung lesion model using the ccRCC cell line UMRC3 stably transfected with GFP and luciferase constructs. This cell line was used for characterization of [18F]FGln uptake and retention by transport analysis in cell culture and by PET/MRI (magnetic resonance imaging) in animal models. Tumor growth in animal models was monitored using bioluminescence (BLI) and MRI. After necropsy, UMRC3 tumor growth in lung tissue was verified by fluorescence imaging and histology.
RESULTS: In UMRC3 cells, [18F]FGln cell uptake was twofold higher than cell uptake in normal kidney HEK293 cells. Tracer cell uptake was reduced by 60-90% in the presence of excess glutamine in the media and by 20-50% upon treatment with V-9302, an inhibitor of the major glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2). Furthermore, in UMRC3 cells, [18F]FGln cell uptake was reduced by siRNA knockdown of ASCT2 to levels obtained by the addition of excess exogenous glutamine. Conversely, [18F]FGln cellular uptake was increased in the presence of the glutaminase inhibitor CB-839. Using simultaneous PET/MRI for visualization, retention of [18F]FGln in vivo in ccRCC lung tumors was 1.5-fold greater than normal lung tissue and twofold greater than muscle. In ccRCC lung tumors, [18F]FGln retention did not change significantly upon treatment with CB-839.
CONCLUSIONS: We report one of the first direct orthotopic mouse models of ccRCC lung lesions. Using PET/MR imaging, lung tumors were easily discerned from normal tissue. Higher uptake of [18F]FGln was observed in a ccRCC cell line and lung lesions compared to HEK293 cells and normal lung tissue, respectively. [18F]FGln cell uptake was modulated by exogenous glutamine, V-9302, siRNA knockdown of ASCT2, and CB-839. Interestingly, in a pilot therapeutic study with CB-839, we observed no difference in treated tumors relative to untreated controls. This was in contrast with cellular studies, where CB-839 increased glutamine uptake.

Keywords:  ASCT2; Glutaminolysis; Kidney cancer; PET/MRI; Renal cell carcinoma lung metastasis; [18F]fluoroglutamine

DOI:  https://doi.org/10.1007/s11307-022-01747-9
Int J Oncol. 2022 Aug;pii: 93. [Epub ahead of print]61(2):

Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review).

Michal Zuzčák, Jan Trnka.

  Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched‑chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.

Keywords:  amino acid metabolism; cancer stem cells; cell metabolism; chemoresistance; glycolysis; metabolic profiling; mitochondrial oxidative metabolism; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3892/ijo.2022.5383
Int J Mol Sci. 2022 Jun 15. pii: 6653. [Epub ahead of print]23(12):

Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells.

Mohammed Razeeth Shait Mohammed, Faisal Alzahrani, Salman Hosawi, Hani Choudhry, Mohammad Imran Khan.

  Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical enzymes of the TCA cycle that produces α-ketoglutarate (αKG). However, their mutated version is well reported in various cancer types, including leukemia, which produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild-type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM), and several hematological malignancies and is correlated with disease progression. This work shows that the treatment of wild-type IDH1 leukemia cells with a specific IDH1 inhibitor shifted leukemic cells toward glycolysis from the oxidative phosphorylation (OXPHOS) phenotype. We also noticed a reduction in αKG in treated cells, possibly suggesting the inhibition of IDH1 enzymatic activity. Furthermore, we found that IDH1 inhibition reduced the metabolites related to one-carbon metabolism, which is essential for maintaining global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor-treated leukemic cells promoted reactive oxygen species (ROS) formation and the loss of mitochondrial membrane potential, leading to apoptosis in leukemic cells. We showed that targeting wild-type IDH1 leukemic cells promotes metabolic alterations that can be exploited for combination therapies for a better outcome.

Keywords:  OXPHOS; glutamine metabolism; metabolomics; reactive oxygen species; wild-type IDH1

DOI:  https://doi.org/10.3390/ijms23126653
Cancer Sci. 2022 Jun 22.

Silybin suppresses ovarian cancer cell proliferation by inhibiting isocitrate dehydrogenase 1 activity.

Zibo Wei, Shuangyan Ye, Haipeng Feng, Chong Zeng, Xinhuai Dong, Xiaokang Zeng, Liming Zeng, Xu Lin, Qiuzhen Liu, Jie Yao.

  Metabolic reprogramming is a sign of malignant tumors, and targeting the metabolism of tumor cells has become a promising therapeutic approach. Here, we report that the Silybin (a nontoxic flavonoid commonly used liver protection) exhibits prominent anti-tumor effects on human ovarian cancer cells. Treatment of an ovarian cancer cell line with Silybin interfered with glutamine metabolism and the tricarboxylic acid cycle. We applied the drug affinity responsive target stability approach to show that Silybin binds to isocitrate dehydrogenase 1 (IDH1). This combination leads to reduced phosphorylation of IDH1 and inhibits enzyme activity. IDH1 dysfunction significantly increases the ratio of NADP/NADPH in the cell, causing an increase in reactive oxygen species (ROS) generation. Immunohistochemistry demonstrated that IDH1 was increased in samples of ovarian cancer compared with normal para-tumoral tissues. Xenograft murine experiments indicated that orally administered Silybin suppressed growth of the tumor formed by ovarian cancer cells. In combination, our data strongly suggest Silybin targets IDH1 in ovarian cancer cells and it may provide a novel treatment candidate.

Keywords:  Ovarian cancer; cancer plasticity; energy metabolism reprogramming; redox homeostasis; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.15470
Free Radic Biol Med. 2022 Jun 16. pii: S0891-5849(22)00452-X. [Epub ahead of print]188 92-102

Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells.

Jingqi Fang, Yini Zhang, Akos A Gerencser, Martin D Brand.

  The rates of formation of superoxide and hydrogen peroxide at different electron-donating sites in isolated mitochondria are critically dependent on the substrates that are added, through their effects on the reduction level of each site and the components of the protonmotive force. However, in intact cells the acute effects of added substrates on different sites of cytosolic and mitochondrial hydrogen peroxide production are unclear. Here we tested the effects of substrate addition on cytosolic and mitochondrial hydrogen peroxide release from intact AML12 liver cells. In 30-min starved cells replete with endogenous substrates, addition of glucose, fructose, palmitate, alanine, leucine or glutamine had no effect on the rate or origin of cellular hydrogen peroxide release. However, following 150-min starvation of the cells to deplete endogenous glycogen (and other substrates), cellular hydrogen peroxide production, particularly from NADPH oxidases (NOXs), was decreased, GSH/GSSH ratio increased, and antioxidant gene expression was unchanged. Addition of glucose or glutamine (but not the other substrates) increased hydrogen peroxide release. There were similar relative increases from each of the three major sites of production: mitochondrial sites IQ and IIIQo, and cytosolic NOXs. Glucose supplementation also restored ATP production and mitochondrial NAD reduction level, suggesting that the increased rates of hydrogen peroxide release from the mitochondrial sites were driven by increases in the protonmotive force and the degree of reduction of the electron transport chain. Long-term (24 h) glucose or glutamine deprivation also diminished hydrogen peroxide release rate, ATP production rate and (for glucose deprivation) NAD reduction level. We conclude that the rates of superoxide and hydrogen peroxide production from mitochondrial sites in liver cells are insensitive to extra added substrates when endogenous substrates are not depleted, but these rates are decreased when endogenous substrates are lowered by 150 min of starvation, and can be enhanced by restoring glucose or glutamine supply through improvements in mitochondrial energetic state.

Keywords:  Liver; Mitochondria; NOX; ROS; Site III(Qo); Site IQ

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.225
Cancers (Basel). 2022 Jun 16. pii: 2983. [Epub ahead of print]14(12):

α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting.

Yanwu Wang, Ning Shen, Gervase Spurlin, Sovannarith Korm, Sarah Huang, Nicole M Anderson, Leah N Huiting, Hudan Liu, Hui Feng.

  Despite the development of metabolism-based therapy for a variety of malignancies, resistance to single-agent treatment is common due to the metabolic plasticity of cancer cells. Improved understanding of how malignant cells rewire metabolic pathways can guide the rational selection of combination therapy to circumvent drug resistance. Here, we show that human T-ALL cells shift their metabolism from oxidative decarboxylation to reductive carboxylation when the TCA cycle is disrupted. The α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle regulates oxidative decarboxylation by converting α-ketoglutarate (α-KG) to succinyl-CoA, while isocitrate dehydrogenase (IDH) 1 and 2 govern reductive carboxylation. Metabolomics flux analysis of T-ALL reveals enhanced reductive carboxylation upon genetic depletion of the E2 subunit of KGDHC, dihydrolipoamide-succinyl transferase (DLST), mimicking pharmacological inhibition of the complex. Mechanistically, KGDHC dysfunction causes increased demethylation of nuclear DNA by α-KG-dependent dioxygenases (e.g., TET demethylases), leading to increased production of both IDH1 and 2. Consequently, dual pharmacologic inhibition of the TCA cycle and TET demethylases demonstrates additive efficacy in reducing the tumor burden in zebrafish xenografts. These findings provide mechanistic insights into how T-ALL develops resistance to drugs targeting the TCA cycle and therapeutic strategies to overcome this resistance.

Keywords:  DNA demethylation; T-cell acute lymphoblastic leukemia; TCA cycle; oxidative phosphorylation; reductive carboxylation; α-ketoglutarate

DOI:  https://doi.org/10.3390/cancers14122983
Med Oncol. 2022 Jun 20. 39(9): 132

Identification of oncogenic signaling pathways associated with the dimorphic metabolic dysregulations in gastric cancer subtypes.

Karthik Balakrishnan, Kumaresan Ganesan.

  Metabolic dysregulations have been identified as intrinsic hallmarks of cancer cells. Investigations of altered metabolic processes, in the context of the associated oncogenic signaling pathways are expected to pave way for the development of targeted cancer therapeutics. We have recently identified the enrichment of glucose and glutamine metabolism in a subset of intestinal subtype gastric tumors at the level of expression of genes, gene sets and the occurrence of metabolites. On the other hand, glucose transport, glucan and fatty acid metabolism were enriched in a subset of diffuse subtype gastric tumors. In the current study, along with glucose metabolism, mTOR, HSP90, MYC, E2F, P53 and proteasome pathways were found enriched in a subset of intestinal subtype and a part of MSI subtype gastric tumors. On the other hand, along with fatty acid metabolism, the oncogenic pathway KRAS was found to be enriched in a subset of GS tumors among diffuse subtype gastric tumors. Thus, oncogenic signaling pathways associated with two distinct metabolic rewiring which differentially occurs between major gastric cancer subtypes were identified. These pathways seem the potential targets to differentially target these gastric cancer subtypes. Exploratory integrative genomic analyses reveal HSP90 inhibitors, AKT/mTOR inhibitors, and cell cycle inhibitors as potential agents to target the gastric tumors with the rewired glucose metabolism and MEK/MAPK inhibitors as suitable drug candidates to target the diffuse subtype tumors with the dysregulated fatty acid metabolism. This observation would pave way for the selective and targeted use of signaling pathway modulators for targeted and stratified gastric cancer therapeutics.

Keywords:  Fatty acid metabolism; Gastric cancer; Glucose metabolism; HSP90 inhibitors; KRAS

DOI:  https://doi.org/10.1007/s12032-022-01717-9
Metabolites. 2022 Jun 17. pii: 558. [Epub ahead of print]12(6):

Metabolic Profiling of Bladder Cancer Patients' Serum Reveals Their Sensitivity to Neoadjuvant Chemotherapy.

Juntao Zhuang, Xiao Yang, Qi Zheng, Kai Li, Lingkai Cai, Hao Yu, Jiancheng Lv, Kexin Bai, Qiang Cao, Pengchao Li, Haiwei Yang, Junsong Wang, Qiang Lu.

  Numerous patients with muscle-invasive bladder cancer develop low responsiveness to cisplatin. Our purpose was to explore differential metabolites derived from serum in bladder cancer patients treated with neoadjuvant chemotherapy (NAC). Data of patients diagnosed with cT2-4aNxM0 was collected. Blood samples were retained prospectively before the first chemotherapy for untargeted metabolomics by 1H-NMR and UPLC-MS. To identify characterized metabolites, multivariate statistical analyses were applied, and the intersection of the differential metabolites discovered by the two approaches was used to identify viable biomarkers. A total of 18 patients (6 NAC-sensitive patients and 12 NAC-resistant patients) were enrolled. There were 29 metabolites detected by 1H-NMR and 147 metabolites identified by UPLC-MS. Multivariate statistics demonstrated that in the sensitive group, glutamine and taurine were considerably increased compared to their levels in the resistant group, while glutamate and hypoxanthine were remarkably decreased. Pathway analysis and enrichment analysis showed significant alterations in amino acid pathways, suggesting that response to chemotherapy may be related to amino acid metabolism. In addition, hallmark analysis showed that DNA repair played a regulatory role. Overall, serum metabolic profiles of NAC sensitivity are significantly different in bladder cancer patients. Glycine, hypoxanthine, taurine and glutamine may be the potential biomarkers for clinical treatment. Amino acid metabolism has potential value in enhancing drug efficacy.

Keywords:  1H-NMR; UPLC-MS; bladder cancer; metabolomics; neoadjuvant chemotherapy; serum

DOI:  https://doi.org/10.3390/metabo12060558
Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00707-2. [Epub ahead of print]32(12): R684-R696

Balancing nutrient and energy demand and supply via autophagy.

Congcong He.

Maintaining nutrient and energy homeostasis is crucial for the survival and function of cells and organisms in response to environmental stress. Cells have evolved a stress-induced catabolic pathway, termed autophagy, to adapt to stress conditions such as starvation. During autophagy, damaged or non-essential cellular structures are broken down in lysosomes, and the resulting metabolites are reused for core biosynthetic processes or energy production. Recent studies have revealed that autophagy can target and degrade different types of nutrient stores and produce a variety of metabolites and fuels, including amino acids, nucleotides, lipids and carbohydrates. Here, we will focus on how autophagy functions to balance cellular nutrient and energy demand and supply - specifically, how energy deprivation switches on autophagic catabolism, how autophagy halts anabolism by degrading the protein synthesis machinery, and how bulk and selective autophagy-derived metabolites recycle and feed into a variety of bioenergetic and anabolic pathways during stress conditions. Recent new insights and progress in these areas provide a better understanding of how resource mobilization and reallocation sustain essential metabolic and anabolic activities under unfavorable conditions.

DOI: https://doi.org/10.1016/j.cub.2022.04.071
Mol Carcinog. 2022 Jun 20.

Targeting mitochondrial metabolism for metastatic cancer therapy.

Antonino Passaniti, Myoung Sook Kim, Brian M Polster, Paul Shapiro.

  Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function-selective extracellular signal-regulated kinase-1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.

Keywords:  cancer metastasis; drug mechanisms; kinase signaling; mitochondria; reactive oxygen species; targeting OxPhos

DOI:  https://doi.org/10.1002/mc.23436
Int J Mol Sci. 2022 Jun 07. pii: 6385. [Epub ahead of print]23(12):

Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers.

Sonia Furgiuele, Géraldine Descamps, Lorena Cascarano, Ambre Boucq, Christine Dubois, Fabrice Journe, Sven Saussez.

  The head and neck tumor microenvironment (TME) is highly infiltrated with macrophages. More specifically, tumor-associated macrophages (TAM/M2-like) are one of the most critical components associated with poor overall survival in head and neck cancers (HNC). Two extreme states of macrophage phenotypes are described as conducting pro-inflammatory/anti-tumoral (M1) or anti-inflammatory/pro-tumoral (M2) activities. Moreover, specific metabolic pathways as well as oxidative stress responses are tightly associated with their phenotypes and functions. Hence, due to their plasticity, targeting M2 macrophages to repolarize in the M1 phenotype would be a promising cancer treatment. In this context, we evaluated macrophage infiltration in 60 HNC patients and demonstrated the high infiltration of CD68+ cells that were mainly related to CD163+ M2 macrophages. We then optimized a polarization protocol from THP1 monocytes, validated by specific gene and protein expression levels. In addition, specific actors of glutamine pathway and oxidative stress were quantified to indicate the use of glutaminolysis by M2 and the production of reactive oxygen species by M1. Finally, we evaluated and confirmed the plasticity of our model using M1 activators to repolarize M2 in M1. Overall, our study provides a complete reversible polarization protocol allowing us to further evaluate various reprogramming effectors targeting glutaminolysis and/or oxidative stress in macrophages.

Keywords:  HNSCC; M1 and M2 macrophages; PBMC; THP1; cancer treatment; glutaminolysis; macrophage polarization; metabolism; oxidative stress; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms23126385
J Gastroenterol. 2022 Jun 21.

Targeting autophagy as a therapeutic strategy against pancreatic cancer.

Keisuke Yamamoto, Dosuke Iwadate, Hiroyuki Kato, Yousuke Nakai, Keisuke Tateishi, Mitsuhiro Fujishiro.

  Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.

Keywords:  Anti-tumor immunity; Autophagy; Host autophagy; Lysosome; PDAC

DOI:  https://doi.org/10.1007/s00535-022-01889-1
World J Stem Cells. 2022 May 26. 14(5): 362-364

Inhibition of glutathione metabolism can limit the development of pancreatic cancer.

Pei-Yuan Cai, Mei-Lin Ma, Yang-Fen Zhang, Zi-Xuan Zhou, Yan Wang, Lian-Ping He, Wei Wang.

  Pharmacological inhibitors of glutathione synthesis and circulation, such as buthionine-sulfoximine, inhibit glutathione metabolism. These drugs decrease the aggressiveness of pancreatic cancer, inhibit tumor stem cell survival, and reduce chemotherapy resistance. Nevertheless, buthionine-sulfoximine also decreases the content of glutathione in normal cells, disrupts the balance between reactive oxygen species and glutathione, and eventually induces cell apoptosis. Pancreatic cancer is usually diagnosed at an advanced stage and has a poor prognosis. Consequently, the use of biomarkers to screen high-risk patients can be an effective method.

Keywords:  Cancer stem cells; Chemoresistance; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Redox

DOI:  https://doi.org/10.4252/wjsc.v14.i5.362
Pharmaceutics. 2022 Jun 19. pii: 1303. [Epub ahead of print]14(6):

Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches.

Carla Navarro, Ángel Ortega, Raquel Santeliz, Bermary Garrido, Maricarmen Chacín, Néstor Galban, Ivana Vera, Juan Bautista De Sanctis, Valmore Bermúdez.

  The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.

Keywords:  carbohydrates; energy metabolism; immunotherapy; inflammation; metabolic reprogramming; neoplasms; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics14061303
PLoS Comput Biol. 2022 Jun 24. 18(6): e1009294

A pipeline for the reconstruction and evaluation of context-specific human metabolic models at a large-scale.

Vítor Vieira, Jorge Ferreira, Miguel Rocha.

Constraint-based (CB) metabolic models provide a mathematical framework and scaffold for in silico cell metabolism analysis and manipulation. In the past decade, significant efforts have been done to model human metabolism, enabled by the increased availability of multi-omics datasets and curated genome-scale reconstructions, as well as the development of several algorithms for context-specific model (CSM) reconstruction. Although CSM reconstruction has revealed insights on the deregulated metabolism of several pathologies, the process of reconstructing representative models of human tissues still lacks benchmarks and appropriate integrated software frameworks, since many tools required for this process are still disperse across various software platforms, some of which are proprietary. In this work, we address this challenge by assembling a scalable CSM reconstruction pipeline capable of integrating transcriptomics data in CB models. We combined omics preprocessing methods inspired by previous efforts with in-house implementations of existing CSM algorithms and new model refinement and validation routines, all implemented in the Troppo Python-based open-source framework. The pipeline was validated with multi-omics datasets from the Cancer Cell Line Encyclopedia (CCLE), also including reference fluxomics measurements for the MCF7 cell line. We reconstructed over 6000 models based on the Human-GEM template model for 733 cell lines featured in the CCLE, using MCF7 models as reference to find the best parameter combinations. These reference models outperform earlier studies using the same template by comparing gene essentiality and fluxomics experiments. We also analysed the heterogeneity of breast cancer cell lines, identifying key changes in metabolism related to cancer aggressiveness. Despite the many challenges in CB modelling, we demonstrate using our pipeline that combining transcriptomics data in metabolic models can be used to investigate key metabolic shifts. Significant limitations were found on these models ability for reliable quantitative flux prediction, thus motivating further work in genome-wide phenotype prediction.

DOI: https://doi.org/10.1371/journal.pcbi.1009294
Chemistry. 2022 Jun 21.

On the evolutionary history of the twenty encoded amino acids.

Andreas Kirschning.

  a-Amino acids are essential molecular constituents of life, twenty of which are privileged because they are encoded by the ribosomal machinery. The question remains open as to why this number and why this 20 in particular, an almost philosophical question that cannot be conclusively resolved. They are closely related to the evolution of the genetic code and whether nucleic acids, amino acids, and peptides appeared simultaneously and were available under prebiotic conditions when the first self-sufficient complex molecular system emerged on Earth. This report focuses on prebiotic and metabolic aspects of amino acids and proteins starting with meteorites, followed by their formation, including peptides, under plausible prebiotic conditions, and the major biosynthetic pathways in the various kingdoms of life. Coenzymes play a key role in the present analysis in that amino acid metabolism is linked to glycolysis and different variants of the tricarboxylic acid cycle (TCA, rTCA, and the incomplete horseshoe version) as well as the biosynthesis of the most important coenzymes. Thus, the report opens additional perspectives and facets on the molecular evolution of primary metabolism.

Keywords:  Amino Acids; Genetic code; coenzymes; metabolism; origin of life

DOI:  https://doi.org/10.1002/chem.202201419