bims-glucam 2022-09-25 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–09–25
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Formyl-Peptide Receptor 2 Signaling Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming of Lung Cancer Cells.
Overcoming cisplatin resistance of human lung cancer by sinomenine through targeting the miR-200a-3p-GLS axis.
Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment.
PYCR1 regulates glutamine metabolism to construct an immunosuppressive microenvironment for the progression of clear cell renal cell carcinoma.
NDRG2 inhibits pyruvate carboxylase-mediated anaplerosis and combines with glutamine blockade to inhibit the proliferation of glioma cells.
Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism.
Hsa_circ_0003602 Contributes to the Progression of Colorectal Cancer by Mediating the miR-149-5p/SLC38A1 Axis.
Metabolic changes during prostate cancer development and progression.
Co-ingestion of glutamine and leucine synergistically promotes mTORC1 activation.
A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.
Interplays of glucose metabolism and KRAS mutation in pancreatic ductal adenocarcinoma.
Metabolome and Transcriptome Profiling Reveal Carbon Metabolic Flux Changes in Yarrowia lipolytica Cells to Rapamycin.
Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression.

Antioxidants (Basel). 2022 Aug 29. pii: 1692. [Epub ahead of print]11(9):

Formyl-Peptide Receptor 2 Signaling Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming of Lung Cancer Cells.

Tiziana Pecchillo Cimmino, Ester Pagano, Mariano Stornaiuolo, Gabriella Esposito, Rosario Ammendola, Fabio Cattaneo.

  Glucose and glutamine play a crucial role in the metabolic reprogramming of cancer cells. Proliferating cells metabolize glucose in the aerobic glycolysis for energy supply, and glucose and glutamine represent the primary sources of carbon atoms for the biosynthesis of nucleotides, amino acids, and lipids. Glutamine is also an important nitrogen donor for the production of nucleotides, amino acids, and nicotinamide. Several membrane receptors strictly control metabolic reprogramming in cancer cells and are considered new potential therapeutic targets. Formyl-peptide receptor 2 (FPR2) belongs to a small family of GPCRs and is implicated in many physiopathological processes. Its stimulation induces, among other things, NADPH oxidase-dependent ROS generation that, in turn, contributes to intracellular signaling. Previously, by phosphoproteomic analysis, we observed that numerous proteins involved in energetic metabolism are uniquely phosphorylated upon FPR2 stimulation. Herein, we investigated the role of FPR2 in cell metabolism, and we observed that the concentrations of several metabolites associated with the pentose phosphate pathway (PPP), tricarboxylic acid cycle, nucleotide synthesis, and glutamine metabolism, were significantly enhanced in FPR2-stimulated cells. In particular, we found that the binding of specific FPR2 agonists: (i) promotes NADPH production; (ii) activates the non-oxidative phase of PPP; (iii) induces the expression of the ASCT2 glutamine transporter; (iv) regulates oxidative phosphorylation; and (v) induces the de novo synthesis of pyrimidine nucleotides, which requires FPR2-dependent ROS generation.

Keywords:  NADPH oxidase; formyl-peptide receptors; glucose metabolism; glutamine transporter; metabolic reprogramming; synthesis of pyrimidine nucleotides

DOI:  https://doi.org/10.3390/antiox11091692
J Chemother. 2022 Sep 19. 1-10

Overcoming cisplatin resistance of human lung cancer by sinomenine through targeting the miR-200a-3p-GLS axis.

Xi Liu, Lei Chen, Tao Wang.

  Lung cancer, a malignant disease, is one of the leading causes of patient death. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Currently, chemotherapeutic agents such as cisplatin are widely used against lung cancer. However, development of chemoresistance, which led to poor prognosis and low survival rate greatly limited the clinical applications of cisplatin. Sinomenine (SIN) is a bioactive component of sinomenium acutum. Accumulating evidence revealed SIN exhibits potential anti-tumor activities in various types of cancers. However, the precise molecular mechanisms for the sinomenine-induced anti-cancer effects have not been fully elucidated. Here, we assessed the effects of sinomenine on cisplatin sensitivity in NSCLC cells. The combination of SIN with cisplatin showed synergistically inhibitory effects on lung cancer cells by calculating the combination index (CI value) using the Calcusyn 2.0 software. Moreover, we detected that the glutamine metabolism was significantly suppressed by sinomenine treatments in lung cancer cells. Under low glutamine supply, A549 cells showed less sensitivity to sinomenine treatments. Meanwhile, miR-200a-3p was found to be significantly induced by SIN treatments. We demonstrated a suppressive role of miR-200a-3p on glutamine metabolism. Furthermore, miR-200a-3p was downregulated but the glutamine metabolism was significantly hyperactive in A549 cisplatin resistant cells compared with parental cells. Bioinformatical analysis and luciferase assay demonstrated the glutaminase (GLS), a key enzyme of glutamine metabolism, is the direct target of miR-200a-3p in lung cancer cells. Finally, rescue experiments demonstrated that recovery of GLS in miR-200a-3p overexpressing-cisplatin resistant cells successfully overrode the sinomenine-mediated cisplatin sensitization. In summary, this study revealed a new molecular mechanism for the sinomenine-promoted cisplatin sensitization, contributing to investigating the sinomenine-based therapeutic agents against chemoresistant NSCLC.

Keywords:  NSCLC; cisplatin resistance; glutaminase; glutamine metabolism; miR-200a-3p; sinomenine

DOI:  https://doi.org/10.1080/1120009X.2022.2111490
Cancers (Basel). 2022 Sep 07. pii: 4351. [Epub ahead of print]14(18):

Targeting the Metabolic Rewiring in Pancreatic Cancer and Its Tumor Microenvironment.

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

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with only a few effective therapeutic options. A characteristic feature of PDAC is its unique tumor microenvironment (TME), termed desmoplasia, which shows extensive fibrosis and extracellular matrix deposition, generating highly hypoxic and nutrient-deprived conditions within the tumor. To thrive in this harsh TME, PDAC undergoes extensive metabolic rewiring that includes the altered use of glucose and glutamine, constitutive activation of autophagy-lysosomal pathways, and nutrient acquisition from host cells in the TME. Notably, these properties support PDAC metabolism and mediate therapeutic resistance, including immune suppression. A deeper understanding of the unique metabolic properties of PDAC and its TME may aid in the development of novel therapeutic strategies against this deadly disease.

Keywords:  KRAS; MHC-I; anabolic glucose metabolism; autophagy; glutamine metabolism; glycolysis; hexosamine biosynthesis pathway; immune checkpoint blockade; immune evasion; lysosome; macropinocytosis; metabolic rewiring; pancreatic ductal adenocarcinoma; pentose phosphate pathway; serine biosynthesis pathway; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14184351
Am J Cancer Res. 2022 ;12(8): 3780-3798

PYCR1 regulates glutamine metabolism to construct an immunosuppressive microenvironment for the progression of clear cell renal cell carcinoma.

Xiyi Wei, Xi Zhang, Shuai Wang, Yichun Wang, Chengjian Ji, Liangyu Yao, Ninghong Song.

Metabolic reprogramming is critical for the setup of the tumor microenvironment (TME). Glutamine has slipped into the focus of research of cancer metabolism, but its role in clear cell renal cell carcinoma (ccRCC) remains vague. Our study aimed to investigate the regulatory mechanism of glutamine in ccRCC and its prognostic value. Gene expression profiles and clinical data of ccRCC patients were obtained from The Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus (GEO) database. Kaplan-Meier survival analysis was used for survival analysis. Consensus clustering was used to extract differentially expressed genes (DEGs) related to glutamine metabolism. Functional analyses, including gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA), were conducted to elucidate the functions and pathways involved in these DEGs. The single-sample GSEA and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) methods were applied to estimate the immune infiltration in the TMEs of two clusters. The univariate regression and the least absolute shrinkage and selection operator (LASSO) Cox regression were used to construct a prognostic signature. R software was utilized to analyze the expression levels and prognostic values of genes in ccRCC. A total of 19 glutamine metabolic genes (GMGs) were screened out for differential expression analysis of normal and ccRCC tissues. Based on survival-related GMGs, two glutamine metabolic clusters with different clinical and transcriptomic characteristics were identified. Patients in cluster B exhibited worse survivals, higher immune infiltration scores, more significant immunosuppressive cell infiltration, higher expression levels of immune checkpoints, and more enriched oncogenic pathways. Glutamine metabolic index (GMI) was constructed according to the GMGs and survival data. In addition, the expression levels of GMGs were associated with immune cell infiltration and immune checkpoints in the TME of ccRCC. Among the GMGs, PYCR1 was the most powerful regulator of immune TME. Our analysis revealed higher-level glutamine metabolism in ccRCC patients with a worse prognosis. The GMI could predict the prognosis of ccRCC patients with a high accuracy. GMGs, such as PYCR1, may be exploited to design novel immunotherapies for ccRCC.

Keywords: Cancer metabolism; PYCR1; glutamine; immunotherapy; tumor microenvironment
Am J Cancer Res. 2022 ;12(8): 3729-3744

NDRG2 inhibits pyruvate carboxylase-mediated anaplerosis and combines with glutamine blockade to inhibit the proliferation of glioma cells.

Jiancai Wang, Xiang Sun, Jiayuan Wang, Kun Zhang, Yiyi Yuan, Yan Guo, Libo Yao, Xia Li, Lan Shen.

Due to the rapid proliferation, cancer cells have increased anabolic biosynthesis, which requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the catalysis of pyruvate carboxylase (PC) and glutaminase (GLS) respectively. In GLS-suppressed cancer cells, the PC-mediated pathway for anaplerosis is crucial to maintain cell growth and proliferation. Here, we investigated the regulatory role and molecular mechanism of N-myc downstream-regulated gene 2 (NDRG2) in PC and PC-mediated anaplerosis. NDRG2 interacted with PC and induced the degradation of PC in glutamine-deprived cells. NDRG2 also inhibited the activity of PC and PC-mediated anaplerosis. As a result, NDRG2 significantly inhibited the malignant growth and proliferation of glioma cells in combination with a glutamine antagonist. In addition, NDRG2 more significantly inhibited the protein level of PC in isocitrate dehydrogenase 1 (R132H)-mutant glioma cells than in wild-type glioma cells. These findings indicate that the molecular mechanism of NDRG2 inhibits PC-mediated anaplerosis and collaborates with glutamine antagonist to inhibit the malignant proliferation of glioma cells, thus providing a theoretical and experimental basis for targeting anaplerosis in glioma therapy.

Keywords: NDRG2; anaplerosis; glioma; glutamine; puruvate carboxylase
Biomolecules. 2022 Aug 27. pii: 1189. [Epub ahead of print]12(9):

Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism.

Abhijit Das, Gregory Gauthier-Coles, Stefan Bröer, Caroline D Rae.

  The cerebellum, or "little brain", is often overlooked in studies of brain metabolism in favour of the cortex. Despite this, anomalies in cerebellar amino acid homeostasis in a range of disorders have been reported. Amino acid homeostasis is central to metabolism, providing recycling of carbon backbones and ammonia between cell types. Here, we examined the role of cerebellar amino acid transporters in the cycling of glutamine and alanine in guinea pig cerebellar slices by inhibiting amino acid transporters and examining the resultant metabolism of [1-13C]d-glucose and [1,2-13C]acetate by NMR spectroscopy and LCMS. While the lack of specific inhibitors of each transporter makes interpretation difficult, by viewing results from experiments with multiple inhibitors we can draw inferences about the major cell types and transporters involved. In cerebellum, glutamine and alanine transfer is dominated by system A, blockade of which has maximum effect on metabolism, with contributions from System N. Inhibition of neural system A isoform SNAT1 by MeAIB resulted in greatly decreased metabolite pools and reduced net fluxes but showed little effect on fluxes from [1,2-13C]acetate unlike inhibition of SNAT3 and other glutamine transporters by histidine where net fluxes from [1,2-13C]acetate are reduced by ~50%. We interpret the data as further evidence of not one but several glutamate/glutamine exchange pools. The impact of amino acid transport inhibition demonstrates that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in that part of the brain.

Keywords:  alanine; amino acid transporters; glutamine

DOI:  https://doi.org/10.3390/biom12091189
Gut Liver. 2022 Sep 23.

Hsa_circ_0003602 Contributes to the Progression of Colorectal Cancer by Mediating the miR-149-5p/SLC38A1 Axis.

Rong Wu, Shiyu Tang, Qiuxiao Wang, Pengfei Kong, Fang Liu.

   Background/Aims: We aimed to investigate the role and working mechanism of Homo sapiens circular RNA_0003602 (hsa_circ_0003602) in colorectal cancer (CRC) development.
Methods: The expression of circ_0003602, miR-149-5p, and solute carrier family 38 member 1 (SLC38A1) was detected by quantitative real-time polymerase chain reaction. RNase R assays were conducted to determine the characteristics of circ_0003602. CCK-8 assays, flow cytometry analysis, transwell invasion assays, wound healing assays and tube formation assays were employed to evaluate cell viability, apoptosis, invasion, migration, and angiogenesis. All protein levels were examined by Western blot or immunohistochemistry assay. The glutamine metabolism was monitored by corresponding glutamine, α-ketoglutarate and glutamate assay kits. Dual-luciferase reporter assay was utilized to confirm the targeted combination between miR-149-5p and circ_0003602 or SLC38A1. A xenograft tumor model was established to analyze the role of circ_0003602 in CRC tumor growth in vivo.
Results: Circ_0003602 was upregulated in CRC tissues and cell lines. Circ_0003602 silencing suppressed CRC cell viability, migration, invasion, angiogenesis, and glutaminolysis; induced cell apoptosis in vitro; and blocked tumor growth in vivo. Moreover, circ_0003602 directly interacted with miR-149-5p to negatively regulate its expression, and circ_0003602 knockdown suppressed the malignant behaviors of CRC cells largely by upregulating miR-149-5p. MiR-149-5p directly bound to the 3' untranslated region of SLC38A1 to induce its degradation, and miR-149-5p overexpression reduced the malignant potential of CRC cells largely by downregulating SLC38A1. Circ_0003602 positively regulated SLC38A1 expression by sponging miR-149-5p in CRC cells.
Conclusions: Circ_0003602 knockdown impedes CRC development by targeting the miR-149-5p/SLC38A1 axis, which provides a novel theoretical basis and new insights for CRC treatment.

Keywords:  Circular RNA SMARCC1; Colorectal neoplasms; Glutamine; MIRN149 microRNA; SLC38A1

DOI:  https://doi.org/10.5009/gnl210542
J Cancer Res Clin Oncol. 2022 Sep 23.

Metabolic changes during prostate cancer development and progression.

Alicia-Marie K Beier, Martin Puhr, Matthias B Stope, Christian Thomas, Holger H H Erb.

  Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa.

Keywords:  CRPC; Glutamine; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s00432-022-04371-w
Sci Rep. 2022 Sep 23. 12(1): 15870

Co-ingestion of glutamine and leucine synergistically promotes mTORC1 activation.

Ryoji Yoshimura, Shuichi Nomura.

Leucine (Leu) regulates protein synthesis and degradation via activation of mammalian target of rapamycin complex 1 (mTORC1). Glutamine (Gln) synergistically promotes mTORC1 activation with Leu via glutaminolysis and Leu absorption via an antiporter. However, Gln has also been shown to inhibit mTORC1 activity. To resolve this paradox, we aimed to elucidate the effects of Gln on Leu-mediated mTORC1 activation. We administered Leu, Gln, tryptophan, Leu + Gln, or Leu + tryptophan to mice after 24-h fasting. The mice were then administered puromycin to evaluate protein synthesis and the gastrocnemius muscle was harvested 30 min later. Phosphorylated eukaryotic initiation factor 4E-binding protein 1, 70-kDa ribosomal protein S6 kinase 1, and Unc-51 like kinase 1 levels were the highest in the Leu + Gln group and significantly increased compared with those in the control group; however, Gln alone did not increase the levels of phosphorylated proteins. No difference in glutamate dehydrogenase activity was observed between the groups. Leu concentrations in the gastrocnemius muscle were similar in the Leu-intake groups. Our study highlights a novel mechanism underlying the promotive effect of Gln on Leu-mediated mTORC1 activation, providing insights into the pathway through which amino acids regulate muscle protein metabolism.

DOI: https://doi.org/10.1038/s41598-022-20251-2
Front Immunol. 2022 ;13 926304

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.

Leire Pedrosa, Carles Foguet, Helena Oliveres, Iván Archilla, Marta García de Herreros, Adela Rodríguez, Antonio Postigo, Daniel Benítez-Ribas, Jordi Camps, Miriam Cuatrecasas, Antoni Castells, Aleix Prat, Timothy M Thomson, Joan Maurel, Marta Cascante.

  Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.

Keywords:  biomarker; immune checkpoint-based therapy; immunotherapy; metabolism; precision medicine

DOI:  https://doi.org/10.3389/fimmu.2022.926304
Cell Death Dis. 2022 Sep 24. 13(9): 817

Interplays of glucose metabolism and KRAS mutation in pancreatic ductal adenocarcinoma.

Yu-Huei Liu, Chun-Mei Hu, Yuan-Sheng Hsu, Wen-Hwa Lee.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide. The primary reasons for this are the lack of early detection methods and targeted therapy. Emerging evidence highlights the metabolic addiction of cancer cells as a potential target to combat PDAC. Oncogenic mutations of KRAS are the most common triggers that drive glucose uptake and utilization via metabolic reprogramming to support PDAC growth. Conversely, high glucose levels in the pancreatic microenvironment trigger genome instability and de novo mutations, including KRASG12D, in pancreatic cells through metabolic reprogramming. Here, we review convergent and diverse metabolic networks related to oncogenic KRAS mutations between PDAC initiation and progression, emphasizing the interplay among oncogenic mutations, glucose metabolic reprogramming, and the tumor microenvironment. Recognizing cancer-related glucose metabolism will provide a better strategy to prevent and treat the high risk PDAC population.

DOI: https://doi.org/10.1038/s41419-022-05259-w
J Fungi (Basel). 2022 Sep 06. pii: 939. [Epub ahead of print]8(9):

Metabolome and Transcriptome Profiling Reveal Carbon Metabolic Flux Changes in Yarrowia lipolytica Cells to Rapamycin.

Ziyu Liu, Junjie Tian, Zhengang Miao, Wenxing Liang, Guangyuan Wang.

  Yarrowia lipolytica is an oleaginous yeast for the production of oleochemicals and biofuels. Nitrogen deficiency is beneficial to lipids biosynthesis in Y. lipolytica. Target of rapamycin (TOR) regulates the utilization of nutrients, which is inhibited in nitrogen starvation or by rapamycin treatment. However, under nitrogen-rich conditions, the lipids biosynthesis in Y. lipolytica after inhibition of TOR by rapamycin is elusive. Combining metabolomics and transcriptomics analysis, we found that rapamycin altered multiple metabolic processes of Y. lipolytica grown in nitrogen-rich medium, especially the metabolisms of amino acids and lipids. A total of 176 differentially accumulated metabolites were identified after rapamycin treatment. Rapamycin increased the levels of tryptophan, isoleucine, proline, serine, glutamine, histidine, lysine, arginine and glutamic acid, and decreased the levels of threonine, tyrosine and aspartic acid. Two fatty acids in lipid droplets, stearic acid (down-regulated) and stearidonic acid (up-regulated), were identified. The expression of 2224 genes changed significantly after rapamycin treatment. Further analysis revealed that rapamycin reduced carbon flux through lipids biosynthesis, accompanied by increased carbon flux through fatty acids degradation and amino acid (especially glutamic acid, glutamine, proline and arginine) biosynthesis. The dataset provided here is valuable for understanding the molecular mechanisms of amino acid and lipids metabolisms in oleaginous yeast.

Keywords:  TOR; Yarrowia lipolytica; amino acid; lipids; metabolomics; nitrogen-rich; rapamycin; transcriptomics

DOI:  https://doi.org/10.3390/jof8090939
Cells. 2022 Sep 13. pii: 2857. [Epub ahead of print]11(18):

Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression.

Kevinn Eddy, Mohamad Naser Eddin, Anna Fateeva, Stefano Vito Boccadamo Pompili, Raj Shah, Saurav Doshi, Suzie Chen.

  Cancer is the second leading cause of death, and incidences are increasing globally. Simply defined, cancer is the uncontrolled proliferation of a cell, and depending on the tissue of origin, the cancer etiology, biology, progression, prognosis, and treatment will differ. Carcinogenesis and its progression are associated with genetic factors that can either be inherited and/or acquired and are classified as an oncogene or tumor suppressor. Many of these genetic factors converge on common signaling pathway(s), such as the MAPK and PI3K/AKT pathways. In this review, we will focus on the metabotropic glutamate receptor (mGluR) family, an upstream protein that transmits extracellular signals into the cell and has been shown to regulate many aspects of tumor development and progression. We explore the involvement of members of this receptor family in various cancers that include breast cancer, colorectal cancer, glioma, kidney cancer, melanoma, oral cancer, osteosarcoma, pancreatic cancer, prostate cancer, and T-cell cancers. Intriguingly, depending on the member, mGluRs can either be classified as oncogenes or tumor suppressors, although in general most act as an oncogene. The extensive work done to elucidate the role of mGluRs in various cancers suggests that it might be a viable strategy to therapeutically target glutamatergic signaling.

Keywords:  MAPK; PI3K/AKT; adenylyl cyclase; cancer; glutamate; guanine nucleotide binding–protein coupled receptor; metabolism; metabotropic glutamate receptor; phospholipase C; riluzole

DOI:  https://doi.org/10.3390/cells11182857