bims-glucam 2022-04-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–04–24
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis.
Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
P2X7 Receptor Augments LPS-Induced Nitrosative Stress by Regulating Nrf2 and GSH Levels in the Mouse Hippocampus.
VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression.
Targeting oncometabolism to maximize immunotherapy in malignant brain tumors.
Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.
Mitochondrial and metabolic alterations in cancer cells.
Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism.
Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas.
BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.
The gut microbial metabolite formate exacerbates colorectal cancer progression.

Transl Oncol. 2022 Apr 19. pii: S1936-5233(22)00090-0. [Epub ahead of print]21 101431

Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis.

Masaki Fujimoto, Ritsuko Higashiyama, Hironobu Yasui, Koya Yamashita, Osamu Inanami.

  Glutamine metabolism, known as glutaminolysis, is abnormally activated in many cancer cells with KRAS or BRAF mutations or active c-MYC. Glutaminolysis plays an important role in the proliferation of cancer cells with oncogenic mutations. In this study, we characterized radiation-induced cell death, which was enhanced by glutaminolysis inhibition in non-small cell lung cancer A549 and H460 cell lines with KRAS mutation. A clonogenic survival assay revealed that treatment with a glutaminase inhibitor, CB839, enhanced radiosensitivity. X-irradiation increased glutamate production, mitochondrial oxygen consumption, and ATP production, whereas CB839 treatment suppressed these effects. The data suggest that the enhancement of glutaminolysis-dependent energy metabolism for ATP production is important for survival after X-irradiation. Evaluation of the cell death phenotype revealed that glutaminolysis inhibitory treatment with CB839 or a low-glutamine medium significantly promoted the proliferation of β-galactosidase-positive and IL-6/IL-8 secretory cells among X-irradiated tumor cells, corresponding to an increase in the senescent cell population. Furthermore, treatment with ABT263, a Bcl-2 family inhibitor, transformed senescent cells into apoptotic cells. The findings suggest that combination treatment with a glutaminolysis inhibitor and a senolytic drug is useful for efficient radiotherapy.

Keywords:  Apoptosis; Glutaminolysis; Radiation; Senescence; Senolytic drug

DOI:  https://doi.org/10.1016/j.tranon.2022.101431
Biomolecules. 2022 Apr 14. pii: 580. [Epub ahead of print]12(4):

Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.

Longfei Zhu, Xuanyu Zhu, Yan Wu.

  In recent years, an increasingly more in depth understanding of tumor metabolism in tumorigenesis, tumor growth, metastasis, and prognosis has been achieved. The broad heterogeneity in tumor tissue is the critical factor affecting the outcome of tumor treatment. Metabolic heterogeneity is not only found in tumor cells but also in their surrounding immune and stromal cells; for example, many suppressor cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated T-lymphocytes. Abnormalities in metabolism often lead to short survival or resistance to antitumor therapy, e.g., chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Using the metabolic characteristics of the tumor microenvironment to identify and treat cancer has become a great research hotspot. This review systematically addresses the impacts of metabolism on tumor cells and effector cells and represents recent research advances of metabolic effects on other cells in the tumor microenvironment. Finally, we introduce some applications of metabolic features in clinical oncology.

Keywords:  fatty acid metabolism; glutaminolysis; glycolysis; immunotherapy; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/biom12040580
Antioxidants (Basel). 2022 Apr 13. pii: 778. [Epub ahead of print]11(4):

P2X7 Receptor Augments LPS-Induced Nitrosative Stress by Regulating Nrf2 and GSH Levels in the Mouse Hippocampus.

Duk-Shin Lee, Ji-Eun Kim.

  P2X7 receptor (P2X7R) regulates inducible nitric oxide synthase (iNOS) expression/activity in response to various harmful insults. Since P2X7R deletion paradoxically decreases the basal glutathione (GSH) level in the mouse hippocampus, it is likely that P2X7R may increase the demand for GSH for the maintenance of the intracellular redox state or affect other antioxidant defense systems. Therefore, the present study was designed to elucidate whether P2X7R affects nuclear factor-erythroid 2-related factor 2 (Nrf2) activity/expression and GSH synthesis under nitrosative stress in response to lipopolysaccharide (LPS)-induced neuroinflammation. In the present study, P2X7R deletion attenuated iNOS upregulation and Nrf2 degradation induced by LPS. Compatible with iNOS induction, P2X7R deletion decreased S-nitrosylated (SNO)-cysteine production under physiological and post-LPS treated conditions. P2X7R deletion also ameliorated the decreases in GSH, glutathione synthetase, GS and ASCT2 levels concomitant with the reduced S-nitrosylations of GS and ASCT2 following LPS treatment. Furthermore, LPS upregulated cystine:glutamate transporter (xCT) and glutaminase in P2X7R+/+ mice, which were abrogated by P2X7R deletion. LPS did not affect GCLC level in both P2X7R+/+ and P2X7R-/- mice. Therefore, our findings indicate that P2X7R may augment LPS-induced neuroinflammation by leading to Nrf2 degradation, aberrant glutamate-glutamine cycle and impaired cystine/cysteine uptake, which would inhibit GSH biosynthesis. Therefore, we suggest that the targeting of P2X7R, which would exert nitrosative stress with iNOS in a positive feedback manner, may be one of the important therapeutic strategies of nitrosative stress under pathophysiological conditions.

Keywords:  ASCT2; S-nitrosylated cysteine; glutamate-glutamine cycle; glutaminase; glutamine synthase; glutathione synthetase; iNOS; xCT

DOI:  https://doi.org/10.3390/antiox11040778
J Cell Biochem. 2022 Apr 17.

VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression.

Tomohiro Kawamura, Yuki Takehora, Naoto Hori, Yuki Takakura, Naoto Yamaguchi, Hiroyuki Takano, Noritaka Yamaguchi.

  Vestigial-like family member 3 (VGLL3) is a member of the VGLL family that serves as cofactors for TEA-domain transcription factors. Although VGLL3 is involved in the proliferation of cancer cells, the molecular mechanisms underlying VGLL3-mediated cell proliferation remain largely unknown. In this study, we found that stable expression of VGLL3 in human lung cancer A549 cells affects glutamine metabolism and increases their dependency on de novo nucleotide synthesis for proliferation. Mechanistically, VGLL3 was found to induce the expression of GART, which encodes a trifunctional enzyme that catalyzes de novo purine synthesis from glutamine. GART knockdown and the glycinamide ribonucleotide synthase, aminoimidazole ribonucleotide synthase, and glycinamide ribonucleotide formyltransferase trifunctional protein (GART) inhibitor lometrexol repressed the proliferation and survival of A549 cells stably expressing VGLL3. Mesenchymal breast cancer BT549 cells and MDA-MB-231 cells showed high expression of VGLL3, and VGLL3 knockdown was found to reduce GART expression. Lometrexol also repressed the proliferation of these breast cancer cells, whereas addition of inosine monophosphate, an important metabolite downstream of GART, rescued this repression. Taken together, these results suggest that VGLL3 induces GART expression and thereby confers de novo nucleotide-dependent cell proliferation in cancer cells.

Keywords:  GART protein; cell proliferation; glutamine; lometrexol; nucleotides; phosphoribosylglycinamide formyltransferase; transcription factors

DOI:  https://doi.org/10.1002/jcb.30251
Oncogene. 2022 Apr 16.

Targeting oncometabolism to maximize immunotherapy in malignant brain tumors.

Joshua D Bernstock, Kyung-Don Kang, Neil V Klinger, Hannah E Olsen, Sam Gary, Stacie K Totsch, Gelare Ghajar-Rahimi, David Segar, Eric M Thompson, Victor Darley-Usmar, Bryan T Mott, Luca Peruzzotti-Jametti, Gregory K Friedman.

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

DOI: https://doi.org/10.1038/s41388-022-02312-y
Cell Death Dis. 2022 Apr 19. 13(4): 370

Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.

Xuetian Yue, Jianming Wang, Chun-Yuan Chang, Juan Liu, Xue Yang, Fan Zhou, Xia Qiu, Vrushank Bhatt, Jessie Yanxiang Guo, Xiaoyang Su, Lanjing Zhang, Zhaohui Feng, Wenwei Hu.

LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.

DOI: https://doi.org/10.1038/s41419-022-04820-x
Eur J Cell Biol. 2022 Apr 13. pii: S0171-9335(22)00028-0. [Epub ahead of print]101(3): 151225

Mitochondrial and metabolic alterations in cancer cells.

Jacopo Di Gregorio, Sabrina Petricca, Roberto Iorio, Elena Toniato, Vincenzo Flati.

  Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.

Keywords:  Amino acids; Cancer; Fatty acids; Metabolism; Mitochondria; OXPHOS

DOI:  https://doi.org/10.1016/j.ejcb.2022.151225
Front Genet. 2022 ;13 849040

Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism.

Abhilasha Sharma, Sonam Sinha, Neeta Shrivastava.

  Metabolic alterations are one of the hallmarks of cancer, which has recently gained great attention. Increased glucose absorption and lactate secretion in cancer cells are characterized by the Warburg effect, which is caused by the metabolic changes in the tumor tissue. Cancer cells switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis due to changes in glucose degradation mechanisms, a process known as "metabolic reprogramming". As a result, proteins involved in mediating the altered metabolic pathways identified in cancer cells pose novel therapeutic targets. Hypoxic tumor microenvironment (HTM) is anticipated to trigger and promote metabolic alterations, oncogene activation, epithelial-mesenchymal transition, and drug resistance, all of which are hallmarks of aggressive cancer behaviour. Angiogenesis, erythropoiesis, glycolysis regulation, glucose transport, acidosis regulators have all been orchestrated through the activation and stability of a transcription factor termed hypoxia-inducible factor-1 (HIF-1), hence altering crucial Warburg effect activities. Therefore, targeting HIF-1 as a cancer therapy seems like an extremely rational approach as it is directly involved in the shift of cancer tissue. In this mini-review, we present a brief overview of the function of HIF-1 in hypoxic glycolysis with a particular focus on novel therapeutic strategies currently available.

Keywords:  cancer; cancer therapies; clinical outcomes; genomic alterations; hypoxia-induced tumor microenvironment; metabolic reprogramming; metabolism; warburg effect

DOI:  https://doi.org/10.3389/fgene.2022.849040
Front Oncol. 2022 ;12 850401

Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas.

Anna Mária Tőkés, Stefan Vári-Kakas, Janina Kulka, Beáta Törőcsik.

  Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients' survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.

Keywords:  anthracycline; breast carcinoma; glucose and lipid metabolism; neoadjuvant and adjuvant chemotherapy; taxane

DOI:  https://doi.org/10.3389/fonc.2022.850401
Antioxidants (Basel). 2022 Mar 29. pii: 661. [Epub ahead of print]11(4):

BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.

Yang Lv, Xiaotong Lv, Jiahui Zhang, Guozhen Cao, Changzhi Xu, Buchang Zhang, Wenchu Lin.

  Accumulating evidence has witnessed the Kelch-like ECH-associated protein 1(KEAP1)- nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis is the main regulatory factor of cell resistance to endogenous and exogenous oxidative assaults. However, there are few studies addressing the upstream regulatory factors of KEAP1. Herein, bioinformatic analysis suggests bromodomain-containing protein 4 (BRD4) as a potential top transcriptional regulator of KEAP1 in lung cancer. Using molecular and pharmacological approaches, we then discovered that BRD4 can directly bind to the promoter of KEAP1 to activate its transcription and down-regulate the stability of Nrf2 which in turn transcriptionally suppresses glucose-6-phosphate dehydrogenase (G6PD) in small cell lung cancer (SCLC), a highly proliferative and aggressive disease with limited treatment options. In addition, BRD4 could associate with the Nrf2 protein in a non-KEAP1-dependent manner to inhibit Nrf2 activity. Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.

Keywords:  BRD4; KEAP1; Nrf2; pentose phosphate pathway; small cell lung cancer

DOI:  https://doi.org/10.3390/antiox11040661
Nat Metab. 2022 Apr 18.

The gut microbial metabolite formate exacerbates colorectal cancer progression.

Dominik Ternes, Mina Tsenkova, Vitaly Igorevich Pozdeev, Marianne Meyers, Eric Koncina, Sura Atatri, Martine Schmitz, Jessica Karta, Maryse Schmoetten, Almut Heinken, Fabien Rodriguez, Catherine Delbrouck, Anthoula Gaigneaux, Aurelien Ginolhac, Tam Thuy Dan Nguyen, Lea Grandmougin, Audrey Frachet-Bour, Camille Martin-Gallausiaux, Maria Pacheco, Lorie Neuberger-Castillo, Paulo Miranda, Nikolaus Zuegel, Jean-Yves Ferrand, Manon Gantenbein, Thomas Sauter, Daniel Joseph Slade, Ines Thiele, Johannes Meiser, Serge Haan, Paul Wilmes, Elisabeth Letellier.

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.

DOI: https://doi.org/10.1038/s42255-022-00558-0