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Current Protein & Peptide Science 2022Cellular metabolic reprogramming driven by oncogenic mutations is considered as a hallmark in the development of malignant cells, and has been a focus over the past... (Review)
Review
Cellular metabolic reprogramming driven by oncogenic mutations is considered as a hallmark in the development of malignant cells, and has been a focus over the past decade. A common theme emerging from these metabolic alterations is that tumor cells can acquire necessary nutrients from a nutrient-limited microenvironment and utilize them to sustain growth and unrestrained cellular division. However, this significant metabolic flexibility and the hostile microenvironment caused by the insufficient vascular exchange, depletion of nutrients, hypoxia, and accumulation of waste products, can inhibit the metabolism and immune activity of tumor-infiltrating lymphocytes and impose barriers to effective antitumor immunotherapies. In this perspective, we review the classical alterations in tumorigenesis- associated metabolic reprogramming and examine the functional contribution of these aberrant metabolisms to the establishment and maintenance of an immunosuppressive microenvironment. Furthermore, we explore the possible approaches to targeting on these metabolic pathways to achieve antitumor immunotherapy, as well as some hypothetical or ongoing combination therapeutic strategies that could, to a certain extent, biologically rationalize and broaden the utility of immune checkpoint inhibitors. Ultimately, we elucidate some dietary modifications that can limit tumor-specific nutritional requirements and maximize the cytotoxicity of other antineoplastic drugs.
Topics: Humans; Tumor Microenvironment; Energy Metabolism; Immunotherapy; Neoplasms; Antineoplastic Agents; Immunologic Factors
PubMed: 35726423
DOI: 10.2174/1389203723666220620161742 -
Trends in Biochemical Sciences Nov 2023Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic... (Review)
Review
Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic cues, as well as during cell differentiation and stress. The concept of homeoviscous adaptation has become a textbook example of membrane responsiveness. Here, we discuss limitations and common misconceptions revolving around it. By highlighting key moments in the life cycle of a transmembrane protein, we illustrate that membrane thickness and a finely regulated membrane compressibility are crucial to facilitate proper membrane protein insertion, function, sorting, and inheritance. We propose that the unfolded protein response (UPR) provides a mechanism for endoplasmic reticulum (ER) membrane homeostasis by sensing aberrant transverse membrane stiffening and triggering adaptive responses that re-establish membrane compressibility.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Homeostasis; Endoplasmic Reticulum; Membrane Proteins
PubMed: 37652754
DOI: 10.1016/j.tibs.2023.08.004 -
International Review of Cell and... 2023Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the... (Review)
Review
Fatty acid metabolic reprogramming has emerged as a major regulator of anti-tumor immune responses with large body of evidence that demonstrate its ability to impact the differentiation and function of immune cells. Therefore, depending on the metabolic cues that stem in the tumor microenvironment, the tumor fatty acid metabolism can tilt the balance of inflammatory signals to either promote or impair anti-tumor immune responses. Oxidative stressors such as reactive oxygen species generated from radiation therapy can rewire the tumor energy supply, suggesting that radiation therapy can further perturb the energy metabolism of a tumor by promoting fatty acid production. In this review, we critically discuss the network of fatty acid metabolism and how it regulates immune response especially in the context of radiation therapy.
Topics: Humans; Energy Metabolism; Neoplasms; Tumor Microenvironment; Lipid Metabolism; Fatty Acids
PubMed: 36997267
DOI: 10.1016/bs.ircmb.2023.01.003 -
Cells Dec 2019The myeloid lineage consists of multiple immune cell types, such as macrophages, monocytes, and dendritic cells. It actively participates in both innate and adaptive... (Review)
Review
The myeloid lineage consists of multiple immune cell types, such as macrophages, monocytes, and dendritic cells. It actively participates in both innate and adaptive immunity. In response to pro- or anti-inflammatory signals, these cells undergo distinct programmed metabolic changes especially in mitochondria. Pro-inflammatory signals induce not only a simple shift from oxidative phosphorylation to glycolysis, but also complicated metabolic alterations during the early and tolerant stages in myeloid cells. In mitochondria, a broken Krebs cycle leads to the accumulation of two metabolites, citrate and succinate, both of which trigger pro-inflammatory responses of myeloid cells. A deficient electron transport chain induces pro-inflammatory responses in the resting myeloid cells while it suppresses these responses in the polarized cells during inflammation. The metabolic reprogramming in mitochondria is also associated with altered mitochondrial morphology. On the other hand, intact oxidative phosphorylation is required for the anti-inflammatory functions of myeloid cells. Fatty acid synthesis is essential for the pro-inflammatory effect and glutamine metabolism in mitochondria exhibits the anti-inflammatory effect. A few aspects of metabolic reprogramming remain uncertain, for example, glycolysis and fatty acid oxidation in anti-inflammation. Overall, metabolic reprogramming is an important element of immune responses in myeloid cells.
Topics: Adaptive Immunity; Citric Acid Cycle; Glycolysis; Humans; Immunity, Innate; Mitochondria; Myeloid Cells; Oxidative Phosphorylation
PubMed: 31861356
DOI: 10.3390/cells9010005 -
Genes Feb 2022Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms... (Review)
Review
Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms underlying variable drug responses. The identification of DNA variants which markedly contribute to inter-individual variations in drug responses would improve the efficacy of treatments and decrease the rate of the adverse side effects of drugs. This review focuses only on the impact of polymorphisms within drug-metabolizing enzymes on drug responses. Anticancer drugs usually have a very narrow therapeutic index; therefore, it is very important to use appropriate doses in order to achieve the maximum benefits without putting the patient at risk of life-threatening toxicities. However, the adjustment of the appropriate dose is not so easy, due to the inheritance of specific polymorphisms in the genes encoding the target proteins and drug-metabolizing enzymes. This review presents just a few examples of such polymorphisms and their impact on the response to therapy.
Topics: Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Pharmacogenetics; Polymorphism, Genetic
PubMed: 35205356
DOI: 10.3390/genes13020311 -
The Proceedings of the Nutrition Society Aug 2019This review examines the metabolic adaptations that occur in response to negative energy balance and their potential putative or functional impact on appetite and food... (Review)
Review
This review examines the metabolic adaptations that occur in response to negative energy balance and their potential putative or functional impact on appetite and food intake. Sustained negative energy balance will result in weight loss, with body composition changes similar for different dietary interventions if total energy and protein intake are equated. During periods of underfeeding, compensatory metabolic and behavioural responses occur that attenuate the prescribed energy deficit. While losses of metabolically active tissue during energy deficit result in reduced energy expenditure, an additional down-regulation in expenditure has been noted that cannot be explained by changes in body tissue (e.g. adaptive thermogenesis). Sustained negative energy balance is also associated with an increase in orexigenic drive and changes in appetite-related peptides during weight loss that may act as cues for increased hunger and food intake. It has also been suggested that losses of fat-free mass (FFM) could also act as an orexigenic signal during weight loss, but more data are needed to support these findings and the signalling pathways linking FFM and energy intake remain unclear. Taken together, these metabolic and behavioural responses to weight loss point to a highly complex and dynamic energy balance system in which perturbations to individual components can cause co-ordinated and inter-related compensatory responses elsewhere. The strength of these compensatory responses is individually subtle, and early identification of this variability may help identify individuals that respond well or poorly to an intervention.
Topics: Appetite; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Humans; Obesity; Weight Loss
PubMed: 30777142
DOI: 10.1017/S0029665118002811 -
Cell Death and Differentiation Feb 2021Perturbation of metabolism elicits cellular stress which profoundly modulates the cellular proteome and thus protein homeostasis (proteostasis). Consequently, changes in... (Review)
Review
Perturbation of metabolism elicits cellular stress which profoundly modulates the cellular proteome and thus protein homeostasis (proteostasis). Consequently, changes in the cellular proteome due to metabolic shift require adaptive mechanisms by molecular protein quality control. The mechanisms vitally controlling proteostasis embrace the entire life cycle of a protein involving translational control at the ribosome, chaperone-assisted native folding, and subcellular sorting as well as proteolysis by the proteasome or autophagy. While metabolic imbalance and proteostasis decline have been recognized as hallmarks of aging and age-associated diseases, both processes are largely considered independently. Here, we delineate how proteome stability is governed by insulin/IGF1 signaling (IIS), mechanistic target of Rapamycin (TOR), 5' adenosine monophosphate-activated protein kinase (AMPK), and NAD-dependent deacetylases (Sir2-like proteins known as sirtuins). This comprehensive overview is emphasizing the regulatory interconnection between central metabolic pathways and proteostasis, indicating the relevance of shared signaling nodes as targets for future therapeutic interventions.
Topics: Aging; Animals; Humans; Protein Folding; Proteolysis; Proteome; Proteostasis; Signal Transduction; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33398091
DOI: 10.1038/s41418-020-00682-y -
Pharmacological Research Jun 2021Mitochondrial unfolded protein response (mitoUPR) is a mitochondria stress response to maintain mitochondrial proteostasis during stress. Increasing evidence suggests... (Review)
Review
Mitochondrial unfolded protein response (mitoUPR) is a mitochondria stress response to maintain mitochondrial proteostasis during stress. Increasing evidence suggests that mitoUPR participates in diverse physiological processes especially metabolism and immunity. Although mitoUPR regulates metabolism in many aspects, it is mainly reflected in the regulation of energy metabolism. During stress, mitoUPR alters energy metabolism via suppressing oxidative phosphorylation (OXPHOS) or increasing glycolysis. MitoUPR also alters energy metabolism and regulates diverse metabolic diseases such as diabetes, cancers, fatty liver and obesity. In addition, mitoUPR also participates in immune process during stress. MitoUPR can induce innate immune response during various infections and may regulate inflammatory response during diverse inflammations. Considering the pleiotropic actions of mitoUPR, mitoUPR may supply diverse therapeutic targets for metabolic diseases and immune diseases.
Topics: Animals; Diabetes Mellitus; Energy Metabolism; Humans; Immunity; Inflammation; Lipid Metabolism; Mitochondrial Proteins; Oxidative Phosphorylation; Unfolded Protein Response
PubMed: 33838292
DOI: 10.1016/j.phrs.2021.105603 -
Experimental & Molecular Medicine Mar 2022It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes... (Review)
Review
It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response.
Topics: Cell Differentiation; Humans; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Sirtuins; T-Lymphocytes
PubMed: 35296782
DOI: 10.1038/s12276-022-00739-7 -
The Journal of Biological Chemistry 2021Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates... (Review)
Review
Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates metabolic processes may provide new opportunities to prevent and treat these epidemics. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a sugar-sensing transcription factor that mediates genomic responses to changes in carbohydrate abundance in key metabolic tissues. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-alpha, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-beta. Carbohydrate metabolites and other metabolic signals may also regulate ChREBP activity via posttranslational modifications including phosphorylation, acetylation, and O-GlcNAcylation that can affect ChREBP's cellular localization, stability, binding to cofactors, and transcriptional activity. In this review, we discuss mechanisms regulating ChREBP activity and highlight phenotypes and controversies in ChREBP gain- and loss-of-function genetic rodent models focused on the liver and pancreatic islets.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Carbohydrate Metabolism; Glucose; Hexoses; Homeostasis; Humans; Islets of Langerhans; Lipid Metabolism; Liver; Mutation; Protein Processing, Post-Translational; Rodentia
PubMed: 33812993
DOI: 10.1016/j.jbc.2021.100623