scholarly journals Glutamine Synthetase as a Therapeutic Target for Cancer Treatment

2021 ◽  
Vol 22 (4) ◽  
pp. 1701
Author(s):  
Go Woon Kim ◽  
Dong Hoon Lee ◽  
Yu Hyun Jeon ◽  
Jung Yoo ◽  
So Yeon Kim ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
De Novo ◽  
Complex Nature ◽  
Critical Function ◽  
Nucleotide Synthesis ◽  
Therapeutic Implications ◽  
Cancer Types ◽  
Glutamine Synthesis

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

scholarly journals Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

2019 ◽  
Vol 20 (18) ◽  
pp. 4507 ◽  
Author(s):  
Lang ◽  
Guerrero-Giménez ◽  
Prince ◽  
Ackerman ◽  
Bonorino ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Stress Proteins ◽  
De Novo ◽  
Human Cancer ◽  
Essential Components ◽  
Wide Range ◽  
Cancer Types ◽  
Shock Proteins

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

scholarly journals The importance of serine metabolism in cancer

2016 ◽  
Vol 214 (3) ◽  
pp. 249-257 ◽  
Author(s):  
Katherine R. Mattaini ◽  
Mark R. Sullivan ◽  
Matthew G. Vander Heiden
Keyword(s):  
Cell Proliferation ◽  
Amino Acid ◽  
Cancer Cells ◽  
De Novo ◽  
Redox Homeostasis ◽  
Cancer Cell Proliferation ◽  
Acid Transport ◽  
Nucleotide Synthesis ◽  
Serine Metabolism

Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer.

scholarly journals Cancer cells are uniquely susceptible to accumulation of MMBIR mutations

2020 ◽  
Author(s):  
Beth Osia ◽  
Thamer Alsulaiman ◽  
Tyler Jackson ◽  
Juraj Kramara ◽  
Suely Oliveira ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metabolic Diseases ◽  
De Novo ◽  
Tumor Evolution ◽  
Template Switching ◽  
Human Genomes ◽  
Normal Human ◽  
Cancer Types ◽  
Lung Adenocarcinomas ◽  
Break Induced Replication

AbstractMicrohomology-mediated break-induced replication (MMBIR) is a mechanism of polymerase template switching at microhomology, which can produce complex genomic rearrangements (CGRs), underlies neurological and metabolic diseases, and contributes to cancer development. Yet, the extent of MMBIR activity in genomes is poorly understood due to difficulty in directly identifying MMBIR events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect MMBIR events in human genomes and report substantial differences in frequency and complexity of MMBIR events between normal and cancer cells. MMBIR events appear only as germline variants in normal human fibroblast cells but readily accumulate de novo across several cancer types. Detailed analysis of MMBIR mutations in lung adenocarcinomas revealed MMBIR-initiated chromosome fusions that disrupted potential tumor suppressor genes and induced CGRs. Our findings document MMBIR as a trigger for widespread genomic instability and highlight MMBIR as a potential driver of tumor evolution.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

scholarly journals Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 688 ◽  
Author(s):  
Elodie Villa ◽  
Eunus Ali ◽  
Umakant Sahu ◽  
Issam Ben-Sahra
Keyword(s):  
Cancer Cells ◽  
Tumor Suppressors ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Cancer Cell Proliferation ◽  
Nucleotide Synthesis ◽  
Nucleotide Pools ◽  
Molecular Determinants ◽  
Target Cancer

Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to support nucleic acid and protein synthesis along with energy preservation, signaling activity, glycosylation mechanisms, and cytoskeletal function. Both oncogenes and tumor suppressors have recently been identified as key molecular determinants for de novo nucleotide synthesis that contribute to the maintenance of homeostasis and the proliferation of cancer cells. Inactivation of tumor suppressors such as TP53 and LKB1 and hyperactivation of the mTOR pathway and of oncogenes such as MYC, RAS, and AKT have been shown to fuel nucleotide synthesis in tumor cells. The molecular mechanisms by which these signaling hubs influence metabolism, especially the metabolic pathways for nucleotide synthesis, continue to emerge. Here, we focus on the current understanding of the molecular mechanisms by which oncogenes and tumor suppressors modulate nucleotide synthesis in cancer cells and, based on these insights, discuss potential strategies to target cancer cell proliferation.

Management of Periocular Neoplasms

2011 ◽  
Author(s):  
Robert C. Kersten
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Treatment Modality ◽  
Frozen Section ◽  
Neck Region ◽  
Complex Nature ◽  
Critical Function ◽  
Medical Practitioners ◽  
Tumor Margins ◽  
Skin Cancers

Epithelial malignancy of the eyelid is a common problem, representing about 14% of skin cancers in the head and neck region. The goals when treating any skin cancer are complete elimination of the tumor and minimal sacrifice of normal adjacent tissues. These concepts are of paramount importance when treating periocular epithelial malignancies because of the complex nature of the periocular tissues and their critical function in protecting the underlying globe, as well as the increased risk that recurrent tumor in this area poses. Many modalities have been advocated, by a variety of medical practitioners, for the treatment of epithelial malignancies in the periocular region. There are two key considerations in selecting a treatment for skin cancers. The first is that the selected modality must be capable of eradicating all tumor cells to which it is applied. The second is that some mechanism must exist to ensure that it is applied to all the existing tumor cells. Because tumors of the lid margins and canthi often exhibit slender strands and shoots of cancer cells that may infiltrate beyond the clinically apparent borders of the neoplasm, appropriate monitoring to ensure that the treatment modality reaches all of the cancer cells is essential. Numerous studies have demonstrated that clinical judgment of tumor margins is inadequate, significantly underestimating the area of microscopic tumor involvement. The introduction of frozen-section control to document adequacy of tumor excision marked a major advancement in the treatment of eyelid malignancies and now represents the standard of care. Any treatment modality that does not use microscopic monitoring of tumor margins must instead encompass a wider area of adjacent normal tissue in hopes that any microscopic extensions of tumor will fall within this area. The purpose of this chapter is to explore alternative methods of periocular cancer treatment. Mohs micrographic technique is a refinement of frozen-section control of tumor borders that, by mapping tumor planes, allows a three-dimensional evaluation of tumor margins rather than the two-dimensional examination provided by routine frozen section. The modality was initiated by Frederick E. Mohs, MD, in 1936.

scholarly journals Control of glutamine synthesis in rat liver

1971 ◽  
Vol 124 (3) ◽  
pp. 653-660 ◽  
Author(s):  
P Lund
Keyword(s):  
Glutamine Synthetase ◽  
De Novo ◽  
Synthetic Medium ◽  
Linear Rate ◽  
Rapid Release ◽  
Initial Release ◽  
Glutamine Synthesis ◽  
Glutamine Production

1. On perfusion of livers from fed rats with a semi-synthetic medium containing no added amino acids there is a rapid release of glutamine during the first 15min (15.6±0.8μmol/h per g wet wt.; mean±s.e.m. of 35 experiments), followed by a low linear rate of production (3.6±0.3μmol/h per g wet wt.; mean±s.e.m. of three experiments). The rapid initial release can be accounted for as wash-out of preexisting intracellular glutamine. 2. Addition of readily permeating substrates, or substrate combinations, giving rise to intracellular glutamate or ammonia, or both, did not appreciably increase the rate of glutamine production over the endogenous rate. The maximum rate obtained was from proline plus alanine; even then the rate represented less than one-fortieth of the capacity of glutamine synthetase measured in vitro. 3. Complete inhibition of respiration in the perfusions [no erythrocytes in the medium; 1mm-cyanide; N2%CO2 (95:5) in the gas phase] or perfusion with glutamine synthetase inhibitors [l-methionine dl-sulphoximine; dl-(%)-allo-δ-hydroxylysine] abolishes the low linear rate of glutamine synthesis, but not the initial rapid release of glutamine. 4. In livers from 48h-starved rats initial release (0–15min) of glutamine was decreased (10.6±1.1μmol/h per g wet wt.; mean±s.e.m. of 11 experiments) and the subsequent rate of glutamine production was lower than in livers from fed rats. Again proline plus alanine was the only substrate combination giving an increase significantly above the endogenous rate. 5. The rate of glutamine synthesis de novo by the liver is apparently unrelated to the tissue content of glutamate or ammonia. 6. The blood glutamine concentration is increased by 50% within 1h of elimination of the liver from the circulation of rats in vivo. 7. There is an output of glutamine by the brain under normal conditions; the mean arterio-venous difference for six rats was 0.023μmol/ml. 8. The high potential activity of liver glutamine synthetase appears to be inhibited by some unknown mechanism: the function of the liver under normal conditions is probably the disposal of glutamine produced by extrahepatic tissues.

scholarly journals Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

2020 ◽  
Author(s):  
Pei-Yun Tsai ◽  
Min-Sik Lee ◽  
Unmesh Jadhav ◽  
Insia Naqvi ◽  
Shariq Madha ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Glutamine Synthetase ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Ductal Adenocarcinoma ◽  
Nutrient Deprivation ◽  
Open Chromatin ◽  
Nucleotide Synthesis ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.

scholarly journals Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

2021 ◽  
Author(s):  
Nicole Kiweler ◽  
Catherine Delbrouck ◽  
Laura Neises ◽  
Vitaly Pozdeev ◽  
Leticia Soriano-Baguet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Carbon Cycle ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
De Novo ◽  
Prolonged Treatment ◽  
Tumor Escape ◽  
Metastatic Progression ◽  
Nucleotide Synthesis

Abstract Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs mainly target the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that enable cell plasticity and foster treatment resistance and tumor escape. Using a panel of anti-cancer drugs, we uncovered that antifolates, despite inducing strong growth arrest, did not impact the cancer cell’s motility potential, indicating that nucleotide synthesis is dispensable for cell motility. Prolonged treatment even selected for more motile cancer subpopulations. We found that cytosolic inhibition of DHFR by MTX only abrogates cytosolic folate cycle, while mitochondrial one-carbon cycle remains highly active. Despite a decreased cellular demand for biomass production, de novo serine synthesis and formate overflow are increased, suggesting that mitochondria provide a protective environment that allows serine catabolism to support cellular motility during nucleotide synthesis inhibition. Enhanced motility of growth-arrested cells was reduced by inhibition of PHGDH-dependent de novo serine synthesis and genetic silencing of mitochondrial one-carbon cycle. In vivo targeting of mitochondrial one-carbon cycle and formate overflow strongly and significantly reduced lung metastasis formation in an orthotopic breast cancer model. In summary, we identified mitochondrial serine catabolism as a targetable, growth-independent metabolic vulnerability to limit metastatic progression.

scholarly journals Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

2021 ◽  
Vol 118 (10) ◽  
pp. e2003014118
Author(s):  
Pei-Yun Tsai ◽  
Min-Sik Lee ◽  
Unmesh Jadhav ◽  
Insia Naqvi ◽  
Shariq Madha ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Glutamine Synthetase ◽  
De Novo ◽  
Ductal Adenocarcinoma ◽  
Nutrient Deprivation ◽  
Open Chromatin ◽  
Nucleotide Synthesis ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.

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