Reprogramming Of Cellular Metabolism Research Articles

Cura Annonae-Chemically Boosting Crop Yields Through Metabolic Feeding of a Plant Signaling Precursor.

The cream of the crop: With the world facing a projected shortfall of crops by 2050, new approaches are needed to boost crop yields. Metabolic feeding of plants with photocaged trehalose-6-phosphate (Tre6P) can increase levels of the signaling metabolite Tre6P in the plant. Reprogramming of cellular metabolism by Tre6P stimulates a program of plant growth and enhanced crop yields, while boosting starch content.

Complement's hidden arsenal: New insights and novel functions inside the cell.

A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.

Regulation of cancer cell metabolism

Dysregulated cellular energetics are an emerging hallmark of cancer cells. The reprogramming of cellular metabolism is critical to maintain survival and limitless proliferation of cancer cells under severe conditions during development. Thus, disordered metabolic pathways, aberrant regulatory molecules, and metabolic enzymes may be potential targets for cancer therapy. This review aims to summarize research progress in cancer metabolism and further describe the relevance of known and unknown metabolic targets in cancer therapy.

Perspectives of Reprogramming Breast Cancer Metabolism.

Reprogramming of cellular metabolism is one of the hallmarks of breast cancer. Breast cancer cells remodel metabolic network to maintain their transformed state and survive in a harsh tumor microenvironment. Dysregulated metabolism further interacts with cellular signaling and epigenetics to promote breast cancer development. Meanwhile, breast cancer stem cells exhibit unique metabolic features, which are critical for therapeutic resistance and tumor recurrence. Besides, aberrant metabolism of breast cancer cells reshapes tumor microenvironment, such as promoting cancer vascularization and sabotaging tumor immunity, to accelerate tumor progression. These special metabolic traits not only open vulnerabilities of breast cancer by targeting essential metabolic pathways but also provide promising diagnostic and prognostic biomarkers to facilitate clinical investigations. Studies in the last few decades have significantly advanced our understanding of mechanisms underlying the reprogramming of breast cancer metabolism and metabolic regulation of breast cancer biology. Targeting tumor metabolism serves as a potentially effective therapeutic approach to suppress breast cancer.

The Glycolytic Switch in Tumors: How Many Players Are Involved?

Reprogramming of cellular metabolism is a hallmark of cancers. Cancer cells more readily use glycolysis, an inefficient metabolic pathway for energy metabolism, even when sufficient oxygen is available. This reliance on aerobic glycolysis is called the Warburg effect, and promotes tumorigenesis and malignancy progression. The mechanisms of the glycolytic shift in tumors are not fully understood. Growing evidence demonstrates that many signal molecules, including oncogenes and tumor suppressors, are involved in the process, but how oncogenic signals attenuate mitochondrial function and promote the switch to glycolysis remains unclear. Here, we summarize the current information on several main mediators and discuss their possible mechanisms for triggering the Warburg effect.

Metabolic Regulation in Mitochondria and Drug Resistance.

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells

Increased breast density attributed to collagen I deposition is associated with a 4–6 fold increased risk of developing breast cancer. Here, we assessed cellular metabolic reprogramming of mammary carcinoma cells in response to increased collagen matrix density using an in vitro 3D model. Our initial observations demonstrated changes in functional metabolism in both normal mammary epithelial cells and mammary carcinoma cells in response to changes in matrix density. Further, mammary carcinoma cells grown in high density collagen matrices displayed decreased oxygen consumption and glucose metabolism via the tricarboxylic acid (TCA) cycle compared to cells cultured in low density matrices. Despite decreased glucose entry into the TCA cycle, levels of glucose uptake, cell viability, and ROS were not different between high and low density matrices. Interestingly, under high density conditions the contribution of glutamine as a fuel source to drive the TCA cycle was significantly enhanced. These alterations in functional metabolism mirrored significant changes in the expression of metabolic genes involved in glycolysis, oxidative phosphorylation, and the serine synthesis pathway. This study highlights the broad importance of the collagen microenvironment to cellular expression profiles, and shows that changes in density of the collagen microenvironment can modulate metabolic shifts of cancer cells.

THERAPEUTIC EFFECT OF TRIDHAM AND 1,2,3,4,6-PENTA-O-GALLOYL-Β-D-GLUCOSE ON ALTERED ENERGY METABOLISM IN MAMMARY CARCINOMA BEARING RATS

ABSTRACT Objective: Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production, and hence, reprogramming of cellular energy metabolism is deemed to be one of the principal hallmarks of cancer. Tridham (TD) has been used by traditional practitioners of Siddha medicine against various ailments. Hence, the present study has been designed to evaluate the therapeutic effect of TD on altered energy metabolism in mammary carcinoma-bearing rats. Methods: Adult female albino rats of Sprague-Dawley strain weighing 170-190 g were used and 7,12-dimethylbenzeneanthracene (DMBA) was used for induction of mammary carcinoma and rats were divided into seven groups. Group I - control rats, Group II - DMBA-induced rats, Group III - DMBA- and TD-treated rats, Group IV - DMBA- and 1,2,3,4,6-Penta-O-galloyl-β-d-glucose (PGG)-treated rats, Group V - DMBA- and cyclophosphamide-treated rats, Groups VI and VII are TD and PGG control rats. Results: Significant (p<0.05) increase in the glycolytic enzymes, hexokinase, phosphoglucoisomerase and aldolase, was observed in tumor-bearing rats whereas gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-biphosphatase, were significantly decreased. The activities of the mitochondrial Krebs cycle enzymes, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase, and respiratory chain enzymes, nicotinamide dinucleotide dehydrogenase and cytochrome c oxidase, were significantly reduced in tumor tissue of the mammary carcinoma-bearing rats. These biochemical disturbances were effectively counteracted by TD and PGG which restore the activities of all these enzymes to the respective control levels. Conclusion: TD and PGG effectively ameliorated the altered glucose metabolism resulting in the regression of breast cancer. Keywords: Breast cancer, Cancer cachexia, Carbohydrate-metabolizing enzymes, Krebs cycle.

Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation.

Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4. Consistent with this, LETM1 silencing caused loss of YAP1 nuclear signal, decreasing the expression of PDGFB, PDGFRB and THBS4. Immunohistochemical staining consistently indicated a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. In clinical data analysis, LETM1 up-regulation in thyroid cancer was found to be related to aggressive tumor features such as lymphovascular invasion (LVI, P < 0.001) and lymph node metastasis (LNM, P = 0.011). Multivariate analysis demonstrated that LETM1 up-regulation increases the risk of LVI and LNM (OR = 3.455, 95% CI = 1.537–7.766 and OR = 3.043, 95% CI = 1.282–7.225, respectively). Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes.

The miR-17∼92 microRNA Cluster Is a Global Regulator of Tumor Metabolism

A central hallmark of cancer cells is the reprogramming of cellular metabolism to meet the bioenergetic and biosynthetic demands of malignant growth. Here, we report that the miR-17∼92 microRNA (miRNA) cluster is an oncogenic driver of tumor metabolic reprogramming. Loss of miR-17∼92 in Myc(+) tumor cells leads to a global decrease in tumor cell metabolism, affecting both glycolytic and mitochondrial metabolism, whereas increased miR-17∼92 expression is sufficient to drive increased nutrient usage by tumor cells. We mapped the metabolic control element of miR-17∼92 to the miR-17 seed family, which influences cellular metabolism and mammalian target of rapamycin complex 1 (mTORC1) signaling through negative regulation of the LKB1 tumor suppressor. miR-17-dependent tuning of LKB1 levels regulates both the metabolic potential of Myc(+) lymphomas and tumor growth invivo. Our results establish metabolic reprogramming as a central function of the oncogenic miR-17∼92 miRNA cluster that drives the progression of MYC-dependent tumors.

Pyruvate dehydrogenase kinase regulates hepatitis C virus replication.

During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication.

Emerging Role and Characterization of Immunometabolism: Relevance to HIV Pathogenesis, Serious Non-AIDS Events, and a Cure.

Immune cells cycle between a resting and an activated state. Their metabolism is tightly linked to their activation status and, consequently, functions. Ag recognition induces T lymphocyte activation and proliferation and acquisition of effector functions that require and depend on cellular metabolic reprogramming. Likewise, recognition of pathogen-associated molecular patterns by monocytes and macrophages induces changes in cellular metabolism. As obligate intracellular parasites, viruses manipulate the metabolism of infected cells to meet their structural and functional requirements. For example, HIV-induced changes in immune cell metabolism and redox state are associated with CD4(+) T cell depletion, immune activation, and inflammation. In this review, we highlight how HIV modifies immunometabolism with potential implications for cure research and pathogenesis of comorbidities observed in HIV-infected patients, including those with virologic suppression. In addition, we highlight recently described key methods that can be applied to study the metabolic dysregulation of immune cells in disease states.

An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense.

The mechanisms that tightly control the transcriptionof host defense genes have not been fully elucidated. We previously identified TFEB as a transcription factor important for host defense, but the mechanisms that regulate TFEB during infection remained unknown. Here, we used C.elegans to discover a pathway that activates TFEB during infection. Gene dkf-1, which encodes a homolog of protein kinase D (PKD), was required for TFEB activation in nematodes infected with Staphylococcus aureus. Conversely, pharmacological activation of PKD wassufficient to activate TFEB. Furthermore, phospholipase C (PLC) gene plc-1 was also required for TFEB activation, downstream of Gαq homolog egl-30 and upstream of dkf-1. Using reverse and chemical genetics, we discovered a similar PLC-PKD-TFEB axis in Salmonella-infected mouse macrophages. In addition, PKCα was required in macrophages. These observations reveal a previously unknown host defense signaling pathway, which has been conserved across one billion years of evolution.

Energy metabolic dysfunction as a carcinogenic factor in cancer cells.

Cancer, as a leading cause of death, has attracted enormous public attention. Reprogramming of cellular energy metabolism is deemed to be one of the principal hallmarks of cancer. In this article, we reviewed the mutual relationships among environmental pollution factors, energy metabolic dysfunction, and various cancers. We found that most environmental pollution factors could induce cancers mainly by disturbing the energy metabolism. By triggering microenvironment alteration, energy metabolic dysfunction can be treated as a factor in carcinogenesis. Thus, we put forward that energy metabolism might be as a key point for studying carcinogenesis and tumor development to propose new methods for cancer prevention and therapy.

CD147 Regulates Cell Metabolism in Pancreatic Cancer via Targeting of Multiple Small Molecule Transporters to the Cell Membrane

CD147 is a highly glycosylated type I transmembrane protein upregulated in pancreatic cancer where it has received significant attention as a potential therapeutic target due to its regulation of several proteins that drive cancer progression. While CD147 was initially thought to act as a ligand on the cell surface to directly stimulate the secretion of several proteins, recent findings have suggested that CD147 may contribute to cancer progression through a much more complex set of interactions. The present study identified CD147 as having a unique chaperone role for multiple transmembrane proteins important for signaling events related to cancer metastasis and metabolic maintenance in pancreatic cancer. A robust combination of cellular, biochemical, proteomic and metabolomic studies showed that CD147 depletion leads to a significant decline in cell proliferation and migration, an increase in epithelial phenotype, and a striking reprogramming of cellular metabolism. Xenograft mouse models further confirmed these findings where tumor growth and metabolism were dependent on CD147 expression. In order to determine the underlying mechanism of CD147's role in pancreatic cancer, we combined crosslinking methods with mass spectrometry to identify the specific interactions and discovered that CD147 is responsible for targeting multiple transmembrane proteins to the cell surface. Furthermore, CD147 depletion caused a down-regulation of a subset of these proteins, which could then be reversed with proteosomal inhibitor treatment indicating that CD147 is a chaperone. Together, our studies illustrate the functional consequence of CD147 expression and chaperone activity in relation to regulating pancreatic cancer progression.

The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer.

Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.

Abstract A1-58: Revisiting cancer energetics: Establishing a link between altered fatty-acid metabolism and metastasis

Abstract Identifying genetic alterations that drive metastatic transformation of cancer cells with enhanced invasiveness and stem cell-like properties is crucial for developing novel therapeutics. Reprogramming of cellular metabolism is an important hallmark of cancer that sustains uncontrolled growth and proliferation. While alterations resulting in elevated glucose uptake and switch to aerobic glycolysis (Warburg effect) have received much attention in recent years, the relevance of fatty-acid (FA) metabolism in cancer progression has remained unclear. Highly aggressive, metastatic tumors resemble stem cells at the genetic and physiological level, and recent studies have revealed a critical role of FA metabolism in providing energy and maintaining the undifferentiated state of stem cells. Moreover, obesity and concurrent elevation in FA levels has been linked to increased mortality rates in cancer patients. These observations raise the possibility of a multi-faceted link between increased availability of FA, altered FA metabolism and cancer progression. Here we investigated the changes in gene expression , mutations and copy number variations in primary and metastatic tumors using a literature-curated set of genes involved in regulating cellular FA uptake, lipogenesis, FA oxidation and the Warburg-effect. Using the pan-cancer TCGA dataset, we showed that &amp;gt;70% of FA oxidation and lipogenesis genes exhibit a significantly higher mutation frequency in metastatic tumors compared to primary tumors. Moreover, &amp;gt;40% of the genes involved in FA uptake showed a significant copy-number gain in metastatic tumors. Next, we performed an association analysis between the gene expression levels of FA metabolism and Warburg effect genes with markers of metastatic progression in the TCGA RNAseq datasets for breast, colorectal, kidney, liver, lung, ovarian and prostate cancers. To score the metastatic potential of individual tumors, we assigned a previously established epithelial-mesenchymal transition gene signature score (EMT score) and then identified a set of co-expressed FA-metabolism genes in each cancer type that shared a concordant association with EMT score. Next, we applied a regression modeling approach utilizing the FA metabolism and Warburg-effect genes to predict the aggressiveness of tumors in each cancer type. We further demonstrated the ability of the gene signature derived from the regression model to accurately predict the aggressiveness of tumors in independent gene expression datasets. Our study established a metabolic gene signature that can predict metastatic potential and may serve as putative therapeutic targets for aggressive tumors. Importantly, this work highlights the crucial association of genetic alterations in FA metabolism with metastasis. Citation Format: Aritro Nath, Christina Chan. Revisiting cancer energetics: Establishing a link between altered fatty-acid metabolism and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-58.

PTTG regulates the metabolic switch of ovarian cancer cells via the c-myc pathway.

Human pituitary tumor-transforming gene (PTTG) is a proto-oncogene involved in the development, invasion, and metastasis of many types of cancer, including ovarian cancer. However, little is known about the role of PTTG in the metabolic shift of ovarian cancer cells. In our study, we show that PTTG expression was positively correlated with the differentiation degree of ovarian cancer tissue. In addition, PTTG suppression by specific shRNA could inhibit the proliferation of ovarian cancer cells A2780 and SKOV-3. Furthermore, aerobic glycolysis was suppressed and oxidative phosphorylation was increased in ovarian cancer cells after PTTG suppression. We further found that the expression of c-myc and several crucial enzymes involved in aerobic glycolysis (e.g., PKM2, LDHA, and glucose transporter 1 (GLUT-1)) were downregulated by PTTG knockwown. Overexpression of c-myc could prevent the metabolic shift induced by PTTG knockwown. Together, our findings suggest that the oncogene PTTG promotes the progression of ovarian cancer cells, and its loss resists tumor development, in part, by regulating cellular metabolic reprogramming that supports cell growth and proliferation via c-myc pathway.

Extensive tissue-specific transcriptomic plasticity in maize primary roots upon water deficit.

Water deficit is the most important environmental constraint severely limiting global crop growth and productivity. This study investigated early transcriptome changes in maize (Zea mays L.) primary root tissues in response to moderate water deficit conditions by RNA-Sequencing. Differential gene expression analyses revealed a high degree of plasticity of the water deficit response. The activity status of genes (active/inactive) was determined by a Bayesian hierarchical model. In total, 70% of expressed genes were constitutively active in all tissues. In contrast, <3% (50 genes) of water deficit-responsive genes (1915) were consistently regulated in all tissues, while >75% (1501 genes) were specifically regulated in a single root tissue. Water deficit-responsive genes were most numerous in the cortex of the mature root zone and in the elongation zone. The most prominent functional categories among differentially expressed genes in all tissues were 'transcriptional regulation' and 'hormone metabolism', indicating global reprogramming of cellular metabolism as an adaptation to water deficit. Additionally, the most significant transcriptomic changes in the root tip were associated with cell wall reorganization, leading to continued root growth despite water deficit conditions. This study provides insight into tissue-specific water deficit responses and will be a resource for future genetic analyses and breeding strategies to develop more drought-tolerant maize cultivars.

Abstract IA22: Regulation of metabolic plasticity in effector T cells

Abstract T lymphocytes are central effectors of the adaptive immune response, and their proper function is critical for long-lasting immunity to foreign pathogens and tumor immunosurveillance. One of the fundamental programs triggered by T cell activation is the reprogramming of cellular metabolism, which is essential to support the bioenergetic and biosynthetic demands of effector T (Teff) cell function. While often considered a “housekeeping” function, cellular metabolism has recently been linked to proper Teff cell differentiation and effector function in vivo, raising the idea that nutrient availability can be immunomodulatory. However, how nutrient availability shapes T cell metabolism and function remains poorly understood. Here we present evidence suggesting that effector T cells possess “metabolic plasticity” and are capable of altering their metabolic programs in response to nutrient availability. We show that T cells possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulates cellular bioenergetics and T cell viability. Effector T cells lacking AMPKα1 display reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we find that AMPKα1 is essential for robust CD4+ and CD8+ T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity. These results and the use AMPK agonists to regulate T cell function will be discussed. Citation Format: Russell Graham Jones. Regulation of metabolic plasticity in effector T cells. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA22.