scholarly journals MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4484
Author(s):  
Vincent Tambay ◽  
Valérie-Ann Raymond ◽  
Marc Bilodeau
Keyword(s):  
Cancer Cell ◽  
Acid Synthesis ◽  
Suppressor Gene ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Phenotype ◽  
Comprehensive Overview ◽  
Amino Acid Synthesis ◽  
Cellular Energetics ◽  
Tumor Suppressor Gene Inactivation

Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

STK11/TP53 co-mutated non-small cell lung cancer (NSCLC) to display a unique tumor microenvironment (TME) and metabolic profile.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9087-9087
Author(s):  
Abdul Rafeh Naqash ◽  
Charalampos S. Floudas ◽  
Asaf Maoz ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Content

9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.

scholarly journals Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype

2018 ◽  
Vol 2018 ◽  
pp. 1-28 ◽  
Author(s):  
Su Yeon Lee ◽  
Min Kyung Ju ◽  
Hyun Min Jeon ◽  
Yig Ji Lee ◽  
Cho Hee Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cell ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Phenotype ◽  
Mesenchymal Transition

Metastasis is a major obstacle to the efficient and successful treatment of cancer. Initiation of metastasis requires epithelial-mesenchymal transition (EMT) that is regulated by several transcription factors, including Snail and ZEB1/2. EMT is closely linked to the acquisition of cancer stem cell (CSC) properties and chemoresistance, which contribute to tumor malignancy. Tumor suppressor p53 inhibits EMT and metastasis by negatively regulating several EMT-inducing transcription factors and regulatory molecules; thus, its inhibition is crucial in EMT, invasion, metastasis, and stemness. Metabolic alterations are another hallmark of cancer. Most cancer cells are more dependent on glycolysis than on mitochondrial oxidative phosphorylation for their energy production, even in the presence of oxygen. Cancer cells enhance other oncogenic metabolic pathways, such as glutamine metabolism, pentose phosphate pathway, and the synthesis of fatty acids and cholesterol. Metabolic reprogramming in cancer is regulated by the activation of oncogenes or loss of tumor suppressors that contribute to tumor progression. Oncogenic metabolism has been recently linked closely with the induction of EMT or CSC phenotypes by the induction of several metabolic enzyme genes. In addition, several transcription factors and molecules involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-β, Wnt, and Akt, regulate oncogenic metabolism. Moreover, p53 induces metabolic change by directly regulating several metabolic enzymes. The collective data indicate the importance of oncogenic metabolism in the regulation of EMT, cell invasion and metastasis, and adoption of the CSC phenotype, which all contribute to malignant transformation and tumor development. In this review, we highlight the oncogenic metabolism as a key regulator of EMT and CSC, which is related with tumor progression involving metastasis and chemoresistance. Targeting oncometabolism might be a promising strategy for the development of effective anticancer therapy.

scholarly journals The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species

2016 ◽  
Vol 80 (1) ◽  
pp. 205-327 ◽  
Author(s):  
Monika Schmoll ◽  
Christoph Dattenböck ◽  
Nohemí Carreras-Villaseñor ◽  
Artemio Mendoza-Mendoza ◽  
Doris Tisch ◽  
...  
Keyword(s):  
Plant Cell Wall ◽  
Light Regulation ◽  
Acid Synthesis ◽  
Effector Proteins ◽  
Comprehensive Overview ◽  
Amino Acid Synthesis ◽  
Trichoderma Species ◽  
Content Type ◽  
Ras Gtpases ◽  
Casein Kinases

SUMMARYThe genusTrichodermacontains fungi with high relevance for humans, with applications in enzyme production for plant cell wall degradation and use in biocontrol. Here, we provide a broad, comprehensive overview of the genomic content of these species for “hot topic” research aspects, including CAZymes, transport, transcription factors, and development, along with a detailed analysis and annotation of less-studied topics, such as signal transduction, genome integrity, chromatin, photobiology, or lipid, sulfur, and nitrogen metabolism inT. reesei,T. atroviride, andT. virens, and we open up new perspectives to those topics discussed previously. In total, we covered more than 2,000 of the predicted 9,000 to 11,000 genes of eachTrichodermaspecies discussed, which is >20% of the respective gene content. Additionally, we considered available transcriptome data for the annotated genes. Highlights of our analyses include overall carbohydrate cleavage preferences due to the different genomic contents and regulation of the respective genes. We found light regulation of many sulfur metabolic genes. Additionally, a new Golgi 1,2-mannosidase likely involved inN-linked glycosylation was detected, as were indications for the ability ofTrichodermaspp. to generate hybrid galactose-containingN-linked glycans. The genomic inventory of effector proteins revealed numerous compounds unique toTrichoderma, and these warrant further investigation. We found interesting expansions in theTrichodermagenus in several signaling pathways, such as G-protein-coupled receptors, RAS GTPases, and casein kinases. A particularly interesting feature absolutely unique toT. atrovirideis the duplication of the alternative sulfur amino acid synthesis pathway.

scholarly journals Modifying metabolically sensitive histone marks by inhibiting glutamine metabolism affects gene expression and alters cancer cell phenotype

Epigenetics ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. 1413-1420 ◽  
Author(s):  
Natalie E. Simpson ◽  
Volodymyr P. Tryndyak ◽  
Marta Pogribna ◽  
Frederick A. Beland ◽  
Igor P. Pogribny
Keyword(s):  
Gene Expression ◽  
Cancer Cell ◽  
Glutamine Metabolism ◽  
Cell Phenotype ◽  
Histone Marks

Influence of increased nutrient supply on Microcystis aeruginosa at cellular and proteomic levels

2020 ◽  
Vol 85 ◽  
pp. 47-58
Author(s):  
Y Jiang ◽  
Y Liu
Keyword(s):  
Microcystis Aeruginosa ◽  
Regulatory Protein ◽  
Acid Synthesis ◽  
Nutrient Supply ◽  
Nitrogen Supply ◽  
Nitrogen And Phosphorus ◽  
Comprehensive Description ◽  
Amino Acid Synthesis ◽  
High Nutrient ◽  
Proteomic Responses

Various studies have observed that increased nutrient supply promotes the growth of bloom-forming cyanobacteria, but only a limited number of studies have investigated the influence of increased nutrient supply on bloom-forming cyanobacteria at the proteomic level. We investigated the cellular and proteomic responses of Microcystis aeruginosa to elevated nitrogen and phosphorus supply. Increased supply of both nutrients significantly promoted the growth of M. aeruginosa and the synthesis of chlorophyll a, protein, and microcystins. The release of microcystins and the synthesis of polysaccharides negatively correlated with the growth of M. aeruginosa under high nutrient levels. Overexpressed proteins related to photosynthesis, and amino acid synthesis, were responsible for the stimulatory effects of increased nutrient supply in M. aeruginosa. Increased nitrogen supply directly promoted cyanobacterial growth by inducing the overexpression of the cell division regulatory protein FtsZ. NtcA, that regulates gene transcription related to both nitrogen assimilation and microcystin synthesis, was overexpressed under the high nitrogen condition, which consequently induced overexpression of 2 microcystin synthetases (McyC and McyF) and promoted microcystin synthesis. Elevated nitrogen supply induced the overexpression of proteins involved in gas vesicle organization (GvpC and GvpW), which may increase the buoyancy of M. aeruginosa. Increased phosphorus level indirectly affected growth and the synthesis of cellular substances in M. aeruginosa through the mediation of differentially expressed proteins related to carbon and phosphorus metabolism. This study provides a comprehensive description of changes in the proteome of M. aeruginosa in response to an increased supply of 2 key nutrients.

O-AcylTEMPOs, a Modified and Fundamental, but Unexplored Carboxylic Derivative: Recent Progress in Synthetic Applications

2019 ◽  
Vol 23 (19) ◽  
pp. 2102-2121
Author(s):  
Hiroyuki Kawafuchi ◽  
Lijian Ma ◽  
Md Imran Hossain ◽  
Tsutomu Inokuchi
Keyword(s):  
Organic Synthesis ◽  
Recent Progress ◽  
Knoevenagel Condensation ◽  
Acid Synthesis ◽  
Amino Acid Synthesis ◽  
Electrophilic Amination ◽  
Weinreb Amides ◽  
Anionic Species ◽  
Diastereoselective Addition ◽  
Carbonyl Function

O-Acylated 2,2,6,6-tetramethylpiperidine-N-oxyls (abbr. O-AcylTEMPOs) are easily available and stable carboxylic derivatives, but their utility in organic synthesis is unexplored in contrast to analogues, such as the N-methoxy-N-methylamides, known as Weinreb amides. Especially, the O–N unit of the O-acylTEMPOs dictates a fairly electronwithdrawing character for the carbonyl function. This enhances the reactivity and stability of the resulting enolate ions. Accordingly, O-acylTEMPOs allow various transformations and this review encompasses seven topics: (1) Reactivity of O-acylTEMPOs towards nucleophiles and chemoselective transformations, (2) Reactivity of anionic species derived from O-acylTEMPOs, (3) E-Selective Knoevenagel condensation of acetoacetylTEMPOs and synthesis of furans, (4) Electrocyclization of 2,4-dienones derived from acetoacetic derivatives and 2-substituted enals, (5) Diastereoselective addition of amide anion to O-(2-alkenoyl)TEMPOs and &#946;-amino acid synthesis, (6) Thermolysis of O-acylTEMPOs, and (7) Applications for Umpolung reactions using O-benzoylTEMPOs, useful for the electrophilic amination of alkenes and alkynes.

scholarly journals Petasis vs. Strecker Amino Acid Synthesis: Convergence, Divergence and Opportunities in Organic Synthesis

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1707
Author(s):  
Wayiza Masamba
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Organic Synthesis ◽  
Acid Synthesis ◽  
Physical Sciences ◽  
Amino Acid Synthesis

α-Amino acids find widespread applications in various areas of life and physical sciences. Their syntheses are carried out by a multitude of protocols, of which Petasis and Strecker reactions have emerged as the most straightforward and most widely used. Both reactions are three-component reactions using the same starting materials, except the nucleophilic species. The differences and similarities between these two important reactions are highlighted in this review.

Sign in / Sign up

Export Citation Format

Share Document