scholarly journals In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Muhammad Mazhar Fareed ◽  
Mohamed A. El-Esawi ◽  
Enas M. El-Ballat ◽  
Gaber El-Saber Batiha ◽  
Abdur Rauf ◽  
...  
Keyword(s):  
Active Sites ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Critical Role ◽  
Phosphoglycerate Mutase ◽  
Cancer Treatments ◽  
Docking Approach ◽  
Cancer Cell Metabolism ◽  
Novel Target ◽  
Ucsf Chimera

Phosphoglycerate mutase 1 (PGAM1) is considered as a novel target for multiple types of cancer drugs for the upregulation in tumor, cell prefoliation, and cell migration. During aerobic glycolysis, PGAM1 plays a critical role in cancer cell metabolism by catalyzing the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG). In this computational-based study, the molecular docking approach was used with the best binding active sites of PGAM1 to screen 5,000 Chinese medicinal phytochemical library. The docking results were three ligands with docking score, RMSD-refine, and residues. Docking scores were -16.57, -15.22, and -15.74. RMSD values were 0.87, 2.40, and 0.98, and binding site residues were Arg 191, Arg 191, Arg 116, Arg 90, Arg 10, and Tyr 92. The best compounds were subjected to ADMETsar, ProTox-2 server, and Molinspiration analysis to evaluate the toxicological and drug likeliness potential of such selected compounds. The UCSF-Chimera tool was used to visualize the results, which shows that the three medicinal compounds named N-Nitrosohexamethyleneimine, Subtrifloralactone-K, and Kanzonol-N in chain-A were successfully binding with the active pockets of PGAM1. The study might facilitate identifying the hit molecules that could be beneficial in the development of antidrugs against various types of cancer treatment. These hit phytochemicals could be beneficial for further investigation of a novel target for cancer.

scholarly journals Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Ma ◽  
Yinsheng Wu ◽  
Shanshan Li ◽  
Xilan Yu
Keyword(s):  
Glucose Metabolism ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
The Novel ◽  
Chromatin Modifications ◽  
Cancer Treatments ◽  
Cancer Cell Metabolism ◽  
Effect Of Glucose

Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.

Pieces of the complex puzzle of cancer cell energy metabolism: an overview of energy metabolism and alternatives for targeted cancer therapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Zeinab Ghasemishahrestani ◽  
Larissa Maura Melo Mattos ◽  
Tatiana Martins Tilli ◽  
André Souza dos Santos ◽  
Marcos Dias Pereira
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Warburg Effect ◽  
Cell Biology ◽  
Aerobic Glycolysis ◽  
Target Therapy ◽  
Cell Metabolism ◽  
Cancer Cell Metabolism

Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called "Warburg effect". Currently, it has been accepted that Warburg effect is not anymore compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused in the bioenergetic and biosynthetic pathways to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrate, amino acids and lipids have already been reported in cancer cells and might play relevant roles for cancer progression. To the best of our knowledge, mostly of these changes are established, mainly due to genetic reprogramming that leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes of high relevance for the energy are targets of oncogenes (ex. PI3K, HIF1 and Myc) and tumor suppressor proteins (ex. p53). As a consequence of the extensive study on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, as well as the influence of genetic reprogramming in cancer cells. In this perspective, we briefly review the cancer cell metabolism (carbohydrate, amino acid and lipid), and also describe oncogenes and tumor suppressors that affect cancer cell metabolism. We also discuss some potential candidates for target therapy to disrupt the main driven-force for cancer cell metabolism and proliferation.

scholarly journals WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

2014 ◽  
Vol 35 (1) ◽  
pp. 2-10 ◽  
Author(s):  
Victoria Sherwood
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cancer Cell ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Critical Role ◽  
Oncogenic Signaling ◽  
Cancer Cell Metabolism ◽  
Oncogenic Signaling Pathways

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

scholarly journals Dynamics of resource allocation in Biological Systems II: On cancer cell metabolism

2016 ◽  
Author(s):  
Imadol V Jeff-Eke
Keyword(s):  
Resource Allocation ◽  
Cancer Cell ◽  
Normal Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Biological Systems ◽  
High Resource ◽  
Resource Requirements ◽  
Initial Work ◽  
Cancer Cell Metabolism

Here we shall apply the approach presented in the paper Dynamics of resource allocation in biological systems in considering resource allocation in cancer cell metabolism, specifically, aerobic glycolysis (Warburg effect). Aerobic glycolysis, the metabolic phenomenon of cells utilizing glucose fermentation to lactate even under conditions of ample oxygen availability. We shall consider resource reallocations between processes of two hypothetical cells: a cancer cell and a normal cell. Specifically, we consider reallocation of resources between cancer-related processes of a cancer cell, normal processes of same cancer cell, and processes of a normal cell in attempts to satisfy the high resource requirements for cancer-related processes. In doing this, we draw inferences from the initial work and state hypotheses as pertains to cancer cell metabolism. From this hypotheses, we shall attempt explanation of Aerobic glycolysis. We end by considering genomic instability as a derivation of cancer cell metabolism.

scholarly journals Dynamics of resource allocation in Biological Systems II: On cancer cell metabolism

2016 ◽  
Author(s):  
Imadol V Jeff-Eke
Keyword(s):  
Resource Allocation ◽  
Cancer Cell ◽  
Normal Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Biological Systems ◽  
High Resource ◽  
Resource Requirements ◽  
Initial Work ◽  
Cancer Cell Metabolism

Here we shall apply the approach presented in the paper Dynamics of resource allocation in biological systems in considering resource allocation in cancer cell metabolism, specifically, aerobic glycolysis (Warburg effect). Aerobic glycolysis, the metabolic phenomenon of cells utilizing glucose fermentation to lactate even under conditions of ample oxygen availability. We shall consider resource reallocations between processes of two hypothetical cells: a cancer cell and a normal cell. Specifically, we consider reallocation of resources between cancer-related processes of a cancer cell, normal processes of same cancer cell, and processes of a normal cell in attempts to satisfy the high resource requirements for cancer-related processes. In doing this, we draw inferences from the initial work and state hypotheses as pertains to cancer cell metabolism. From this hypotheses, we shall attempt explanation of Aerobic glycolysis. We end by considering genomic instability as a derivation of cancer cell metabolism.

Leukemogenic Tyrosine Kinases Inhibit PKM2 to Promote the Warburg Effect and Tumor Growth

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3142-3142
Author(s):  
Taro Hitosugi ◽  
Sumin Kang ◽  
Matthew Vander Heiden ◽  
Tea-wook Chung ◽  
Shannon Elf ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Hematopoietic Malignancies ◽  
Cancer Cell Metabolism ◽  
The Warburg Effect

Abstract Abstract 3142 The Warburg effect describes a pro-oncogenic metabolic switch in which cancer cells, including leukemia cells, take up more glucose than normal tissue, yet use less glucose for oxidative phosphorylation and favor glycolysis even in the presence of oxygen (aerobic glycolysis). However, the molecular mechanisms underlying the Warburg effect remain unclear. Growth factor (GF) receptors are believed to play a key role in programming cancer cell metabolism. These GF receptors are expressed in many hematopoietic malignancies as constitutively activated tyrosine kinase mutants. Thus, we examinined whether tyrosine kinase signaling — commonly upregulated in hematopoietic malignancies — regulates the Warburg effect to contribute to leukemogenesis and disease progression. We performed phospho-proteomics studies and found that pyruvate kinase M2 isoform (PKM2), which is a rate-limiting enzyme of glycolysis, is tyrosine phosphorylated in leukemia cells expressing FGFR1 fusion tyrosine kinases, which are associated with 8p11 leukemia/lymphoma syndrome. We also found that 8p11 leukemogenic FGFR1 directly phosphorylates and inhibits PKM2. Recent seminal studies from Dr. Lew Cantley's group demonstrated that the enzymatic activity of PKM2 is inhibited by phosphotyrosine binding; PKM2 expression is important for aerobic glycolysis and provides a growth advantage to tumors. However, it remains unclear which dedicated tyrosine kinase pathways are physiologically responsible for this regulation and whether PKM2 itself is tyrosine phosphorylated to achieve inhibition of PKM2 in cancer cells. Here we report that FGFR1 inhibits PKM2 by direct phosphorylation at Y105. This consequently inhibits the formation of tetrameric, active PKM2 by disrupting cofactor fructose-1,6-bisphosphate (FBP) binding in a putative “inter-molecule manner”, where one molecule in an active PKM2 tetramer, when phosphorylated, may function as an inhibitory binding partner to the other sister molecules. In addition, phosphorylation of PKM2 at Y105 is common in many human leukemia cell lines expressing oncogenic tyrosine kinases such as BCR-ABL, FLT3-ITD, and JAK2V617F. Furthermore, expression of the PKM2 Y105F mutant in cancer cells following RNAi-mediated knockdown of endogenous PKM2 leads to decreased cell proliferation under hypoxia, increased oxidative phosphorylation with reduced lactate production, and reduced tumor growth in xenograft nude mice. Our findings suggest that tyrosine phosphorylation regulates PKM2 to program cancer cell metabolism and promote tumor growth. This may represent a common, acute molecular mechanism to regulate the Warburg effect, in addition to the chronic changes that are believed to be regulated by hypoxia inducible factor 1 and Myc. Disclosures: No relevant conflicts of interest to declare.

Treatment of breast, ovarian and lung cancer cells by inducing apoptosis with a deep eutectic solvent prepared from 2-deoxy-D-glucose and metformin: Cancer cell metabolism as a drug target.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15599-e15599
Author(s):  
Sauli Vuoti ◽  
Jaakko Eemil ◽  
Kumar Narasimha ◽  
Kai Reinikainen
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Apoptotic Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Deep Eutectic Solvent ◽  
Migration And Invasion ◽  
Solvent Mixtures ◽  
Human Beings ◽  
Cancer Cell Metabolism

e15599 Background: Targeting cancer cell metabolism has gained attention as a future strategy to fight cancer. A characteristic of tumor cells is the elevated aerobic glycolysis for energy production. It has been shown that 2-deoxy-D-glucose (2DG) inhibits glycolysis and induces apoptotic cell death in different tumor types. The anti-diabetic drug metformin has been used in combination to enhance the inhibitory effect. So far, the attempts to combine both compounds in a clinical setting have been limited by the requirement of concentrations higher than those accessible in blood plasma of human beings. Deep eutectic solvents (DES) are solvent mixtures prepared from hydrogen bond donors and acceptors, wherein pharmaceutically active compounds can also be one of the components. Besides having unique physicochemical properties, DESs have been reported to demonstrate or enhance anticancer properties. Methods: We developed a DES mixture from 2DG and MET using a method based in mechanical grinding. We investigated the anticancer activity of conventional and DES mixtures of MET and 2DG, and used the mixtures to inhibit the growth, migration and invasion of cancer cells, and induce cell cycle arrest in vitro. Results: MET and 2DG, alone and in combination, induced apoptosis in the H460, SKOV-3, MDA-MB-231 and HCC1806 (TNBC) cell lines. Induction of apoptosis was further quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. DES mixtures had the highest impact on cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations. The DES mixture with the lowest concentration to induce apoptosis consisted of 100 µM 2DG and 200 µM MET. A conventional solution with similar concentrations showed no activity. Conclusions: We developed a DES from 2DG/MET, which significantly reduced the viability of several types of cancer cells, surpassing the effect of single components or mixtures. The DES does not necessitate the use of additional solvents and could be used to develop clinical applications for targeting cancer cell metabolism.

scholarly journals USP28 promotes aerobic glycolysis of colorectal cancer by increasing stability of FOXC1

2021 ◽  
Author(s):  
Zhaohui Liu ◽  
Min Chen ◽  
Xiaoping Xu ◽  
Lei Zhang ◽  
Yuan Pan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Cancer Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Over Expression ◽  
Cancer Cell Metabolism ◽  
Cancer Tissues

Aerobic glycolysis is essential for cancer cell metabolism and growth. Deubiquitinase, USP28 (ubiquitin specific peptidase 28), could maintain stability of proteins involved in tumor progression. This study was performed to investigate the role of USP28 in aerobic glycolysis of colorectal cancer. Our data showed that USP28 mRNA and protein expressions were enhanced in colorectal cancer tissues and cells. Functional assays demonstrated that overexpression of USP28 promoted cell proliferation and aerobic glycolysis of colorectal cancer, while USP28 inhibition could reverse these effects. Protein expression of Forkhead Box C1 (FOXC1) was increased by USP28 over-expression, whereas knockdown of USP28 aggravated cycloheximide (CHX; protein synthesis inhibitor) stimulated decrease of FOXC1. Moreover, proteasome inhibitor, MG132, could rescue USP28 silence-induced degradation of FOXC1. Overexpression of FOXC1 counteracted the suppressive effects of USP28 interference on colorectal cancer cell viability and aerobic glycolysis. In conclusion, USP28 enhanced cell viability and aerobic glycolysis of colorectal cancer by stabilizing FOXC1, suggesting that USP28-FOXC1 might be a novel therapeutic avenue for colorectal cancer.

scholarly journals TAMI-19. METABOLIC INTERACTIONS BETWEEN TUMOR CELLS AND THE IMMUNE SYSTEM IN GBM: A POTENTIAL ACHILLES HEEL OF GBM FOR NOVEL THERAPEUTICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii217-ii217
Author(s):  
Guimei Tian ◽  
Changlin Yang ◽  
Michael Andrews ◽  
Aida Karachi ◽  
Mariana Dajac ◽  
...  
Keyword(s):  
Immune System ◽  
Lipid Metabolism ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Critical Role ◽  
Acid Uptake ◽  
Metabolic Interactions ◽  
Metabolic Heterogeneity

Abstract INTRODUCTION Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. OBJECTIVES The objectives are to unravel the various molecular signals and metabolic link that underlie the interaction of SCCs with the GBM microenvironment, in particular with the suppressive immune compartment, and to effectively target these interactions for better therapeutics. METHODS Multiple murine glioma cell lines were used to establish metabolic heterogeneity and communications, while various genetic and pharmacological approaches were applied to assess the effect of disrupting the metabolic interplay between SCCs and the immune system. RESULTS We determined that SCCs exhibit distinct metabolic dependencies, involving preferential lipid metabolism supported by enhanced fatty acid uptake. We also found that tumor progression is regulated by the interaction of SCCs with the immune system and established that SCCs recruit immune suppressive M2-like macrophages to the tumor microenvironment, which in turn work against tumor immune rejection by inhibiting T cell anti-tumor activity. The immune microenvironment shaped by SCCs is marked by specific metabolic features enhancing lipid exchange capacities that are exploited by SCCs to support their survival and functions. Importantly, disrupting lipid metabolic exchange sensitized tumors to chemotherapy. CONCLUSION Our results reveal that metabolic interactions between SCCs and tumor-associated macrophages within the GBM microenvironment play a critical role in the development of drug and immune resistant tumors. This study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities.

A Review on Important Histone Acetyltransferase (HAT) Enzymes as Targets for Cancer Therapy

2019 ◽  
Vol 15 (2) ◽  
pp. 120-130
Author(s):  
Mohammad Ghanbari ◽  
Reza Safaralizadeh ◽  
Kiyanoush Mohammadi
Keyword(s):  
Gene Expression ◽  
Histone Acetyltransferase ◽  
Critical Role ◽  
Cancer Treatments ◽  
Control Of Gene Expression ◽  
Post Translational Modifications ◽  
Therapeutic Drugs ◽  
The Status ◽  
Acetyl Group ◽  
Increase Gene Expression

At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.

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