Reprogramming Of Energy Metabolism Research Articles

Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells

ABSTRACT Lacking a self-contained metabolism network, viruses have evolved multiple mechanisms for rewiring the metabolic system of their host to hijack the host’s metabolic resources for replication. Newcastle disease virus (NDV) is a paramyxovirus, as an oncolytic virus currently being developed for cancer treatment. However, how NDV alters cellular metabolism is still far from fully understood. In this study, we show that NDV infection reprograms cell metabolism by increasing glucose utilization in the glycolytic pathway. Mechanistically, NDV induces mitochondrial damage, elevated mitochondrial reactive oxygen species (mROS) and ETC dysfunction. Infection of cells depletes nucleotide triphosphate levels, resulting in elevated AMP:ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and MTOR crosstalk mediated autophagy. In a time-dependent manner, NDV shifts the balance of mitochondrial dynamics from fusion to fission. Subsequently, PINK1-PRKN-dependent mitophagy was activated, forming a ubiquitin chain with MFN2 (mitofusin 2), and molecular receptor SQSTM1/p62 recognized damaged mitochondria. We also found that NDV infection induces NAD+-dependent deacetylase SIRT3 loss via mitophagy to engender HIF1A stabilization, leading to the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Overall, these studies support a model that NDV modulates host cell metabolism through PINK1-PRKN-dependent mitophagy for degrading SIRT3. Abbreviations: AMPK: AMP-activated protein kinase; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECAR: extracellular acidification rate; hpi: hours post infection LC-MS: liquid chromatography-mass spectrometry; mito-QC: mCherry-GFP-FIS1[mt101–152]; MFN2: mitofusin 2; MMP: mitochondrial membrane potential; mROS: mitochondrial reactive oxygen species; MOI: multiplicity of infection; 2-NBDG: 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose; NDV: newcastle disease virus; OCR: oxygen consumption rate; siRNA: small interfering RNA; SIRT3: sirtuin 3; TCA: tricarboxylic acid; TCID50: tissue culture infective doses.

Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

256 Metabolic Vulnerabilities as Predictive Biomarkers and Therapeutic Targets in Skin Carcinogenesis

UVB is the most significant risk factor of non-melanoma skin cancers, like cSCCs, the most common types of human malignancies worldwide. cSCCs are considered to progress from a precursor AK to in situ, invasive and finally metastasis which is associated with a dismal prognosis and a median survival of less than 2 years. Thus, to preserve the chances to cure cSCCs it is urgent to improve the level of prevention and protection for skin cancer with the evaluation of new therapeutic strategies. Energy metabolism reprogramming plays an important role in the initiation and progression of many types of human tumors but little attention has been given to precise the metabolism rewiring and molecular heterogeneity in skin cancers. Using a multistage model of UVB radiation-induced skin cancer and with a quantitative proteomic and targeted metabolomics approaches, we found that specific metabolic modifications occurs at the very early stage of photocarcinogenesis. We showed that the distal part of electron transport chain (ETC) in mitochondria was upregulated in AK owing to the over-activation of dihydroorotate dehydrogenase (DHODH), an enzyme implied in pyrimidine synthesis. Biochemical functional analysis on human cell lines at different stages of carcinogenesis revealed a positive correlation between stages of tumor development with the following features: oxygen consumption rate (OCR), extra cellular acidification rate (ECAR), glutamine consumption rate and the expression levels of enzymes implicated in pyrimidine biosynthesis. We evaluated the DHODH expression level in human skin at different stages of carcinogenesis. Immunostaining showed a positive correlation between the stages of carcinogenesis and the DHODH expression levels. Finally we tested the effect of leflunomide (LFN), a potent DHODH inhibitor, in our xenograft model. Results showed a significant reduction in tumor growth in mice treated with LFN. Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.

Helichrysetin inhibits gastric cancer growth by targeting c-Myc/PDHK1 axis-mediated energy metabolism reprogramming.

Helichrysetin (HEL), a chalcone isolated from Alpinia katsumadai Hayata, has an antitumor activity in human lung and cervical cancers. However, the inhibitory effect and underlying mechanism of HEL in gastric cancer have not been elucidated. Here, HEL significantly inhibited the growth of gastric cancer MGC803 cells in vitro and in vivo. HEL decreased expression and transcriptional regulatory activity of c-Myc and mRNA expression of c-Myc target genes. HEL enhanced mitochondrial oxidative phosphorylation (OXPHOS) and reduced glycolysis as evidenced by increased mitochondrial adenosine triphosphate (ATP) production and excessive reactive oxygen species (ROS) accumulation, and decreased the pPDHA1/PDHA1 ratio and Glyco-ATP production. Pyruvate enhanced OXPHOS after HEL treatment. c-Myc overexpression abolished HEL-induced inhibition of cell viability, glycolysis, and protein expression of PDHK1 and LDHA. PDHK1 overexpression also counteracted inhibitory effect of HEL on cell viability. Conversely, c-Myc siRNA decreased cell viability, glycolysis, and PDHK1 expression. NAC rescued the decrease in viability of HEL-treated cells. Additionally, HEL inhibited the overactivated mTOR/p70S6K pathway in vitro and in vivo. HEL-induced cell viability inhibition was counteracted by an mTOR agonist. mTOR inhibitor also decreased cell viability. Similar results were obtained in SGC7901 cells. HEL repressed lactate production and efflux in MGC803 cells. These results revealed that HEL inhibits gastric cancer growth by targeting mTOR/p70S6K/c-Myc/PDHK1-mediated energy metabolism reprogramming in cancer cells. Therefore, HEL may be a potential agent for gastric cancer treatment by modulating cancer energy metabolism reprogramming.

PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3

Reprogramming of energy metabolism is a hallmarkofcancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood.In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn, which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ)treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.

3D Tumor Models for Breast Cancer: Whither We Are and What We Need.

Three-dimensional (3D) models have led to a paradigm shift in disease modeling in vitro, particularly for cancer. The past decade has seen a phenomenal increase in the development of 3D models for various types of cancers with a focus on studying stemness, invasive behavior, angiogenesis, and chemoresistance of cancer cells, as well as contributions of its stroma, which has expanded our understanding of these processes. Cancer biology is moving into exploring the emerging hallmarks of cancer, such as inflammation, immune evasion, and reprogramming of energy metabolism. Studies into these emerging concepts have provided novel targets and treatment options such as antitumor immunotherapy. However, 3D models that can investigate the emerging hallmarks are few and underexplored. As commonly used immunocompromised mice and syngenic mice cannot accurately mimic human immunology, stromal interactions, and metabolism and require the use of prohibitively expensive humanized mice, there is tremendous scope to develop authentic 3D tumor models in these areas. Taking the specific case of breast cancer, we discuss the currently available 3D models, their applications to mimic signaling in cancer, tumor-stroma interactions, drug responses, and assessment of drug delivery systems and therapies. We discuss the lacunae in the development of 3D tumor models for the emerging hallmarks of cancer, for lesser-explored forms of breast cancer, and provide insights to develop such models. We discuss how the next generation of 3D models can provide a better mimic of human cancer modeling compared to xenograft models and the scope toward preclinical models and precision medicine.

High glucose macrophage exosomes enhance atherosclerosis by driving cellular proliferation & hematopoiesis

SummaryWe investigated whether extracellular vesicles (EVs) produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/− mice with exosomes produced by bone marrow-derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Infusions of BMDM–HG-exo increased hematopoiesis, circulating myeloid cell numbers, and atherosclerotic lesions with an accumulation of macrophage foam and apoptotic cells. Transcriptome-wide analysis of cultured macrophages treated with BMDM–HG-exo or plasma EVs isolated from subjects with type II diabetes revealed a reduced inflammatory state and increased metabolic activity. Furthermore, BMDM–HG-exo induced cell proliferation and reprogrammed energy metabolism by increasing glycolytic activity. Lastly, profiling microRNA in BMDM–HG-exo and plasma EVs from diabetic subjects with advanced atherosclerosis converged on miR-486-5p as commonly enriched and recognized in dysregulated hematopoiesis and Abca1 control. Together, our findings show that EVs serve to communicate detrimental properties of hyperglycemia to accelerate atherosclerosis in diabetes.

PGK1 Is a Key Target for Anti-Glycolytic Therapy of Ovarian Cancer: Based on the Comprehensive Analysis of Glycolysis-Related Genes.

Reprogramming of energy metabolism is a key hallmark of cancer, which provides a new research perspective for exploring the development of cancer. However, the most critical target of anti-glycolytic therapy for ovarian cancer remains unclear. Therefore, in the present study, Oncomine, GEPIA, and HPA databases, combined with clinical specimens of different histological types of ovarian cancer were used to comprehensively evaluate the expression levels of glycolysis-related metabolite transporters and enzymes in ovarian cancer. We selected phosphoglycerate kinase 1 (PGK1), which showed the greatest prognostic value in the Kaplan-Meier Plotter database, for subsequent validation. Immunochemistry assays confirmed that PGK1 was highly expressed in ovarian cancer. The PGK1 expression level was an independent risk factor for the survival and prognosis of patients with ovarian cancer. Functional analysis showed that the PGK1 expression level was positively correlated with the infiltration of neutrophils. Cell experiments confirmed that inhibiting PGK1 expression in ovarian cancer cells could reduce the epithelial-mesenchymal transition (EMT) process, resulting in loss of cell migration and invasion ability. The small molecule NG52 dose-dependently inhibited the proliferation of ovarian cancer cells. In addition, NG52 reduced the EMT process and reversed the Warburg effect by inhibiting PGK1 activity. Therefore, PGK1 is an attractive molecular target for anti-glycolytic therapy of ovarian cancer.

ITRAQ-based quantitative proteomics suggests mitophagy involvement after Rice black-streaked dwarf virus acquisition in insect vector small brown planthopper Laodelphax striatellus Fallén

Plant viruses trigger numerous responses in their insect vectors. Using iTRAQ-based quantitative proteomics analysis, early responses of the insect vector, the small brown planthopper (Laodelphax striatellus Fallén, SBPH), after acquiring Rice black-streaked dwarf virus (RBSDV) at 3 days and 5 days post first access to diseased plants (padp) were revealed. A total of 582 differentially abundant proteins (DAPs) in SBPH with a fold change >1.500 or <0.667 (p-value < 0.05) were identified. The proteomic analysis in SBPH at 3 days padp revealed 106 highly abundant proteins and 193 of low abundance, while 5 days padp revealed 214 highly abundant proteins and 182 of low abundance. Among them, 51 highly abundant proteins and 42 of low abundance were shown consistently at both 3 days and 5 days padp. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis mapping and Gene Ontology (GO) term classification suggested impairment of mitochondria in SBPH after RBSDV acquisition, and the 77 out of 582 differentially abundant SBPH proteins analyzed by the STRING program revealed the interaction network of the mitochondrial DAPs, showing an overall down-regulation of mitochondrial proteins including the electron transport chain proteins and mitochondrial ribosome proteins. The high abundance of Parkin at 5 days padp suggests that activation of mitophagy induced degradation of mitochondria occurred. Further verification of autophagy/mitophagy-related genes by reverse-transcription quantitative RT-PCR (RT-qPCR) in SBPH after RBSDV acquisition showed up-regulation of the autophagy receptors Optineurin (OPTN), Sequestosome-1 (SQSTM1, also known as p62) and Tax1-binding protein 1 (TAX1BP1) which targets ubiquitinated damaged mitochondria during mitophagy. The phosphorylation of the three autophagy receptors may be up-regulated through an increase of transcription level TRAF-associated NFκB activator (TANK)-binding kinase 1 (TBK1). As a result, an overall reduction in the abundance of mitochondrial proteins was observed and the selective autophagic degradation was up-regulated through increased transcription level of OPTN, p62/SQSTM1, TAX1BP1 and TBK1. Therefore, acquisition of RBSDV associated with up-regulated autophagy and selective mitochondrial degradation in SBPH suggest prevention of mitochondrial-mediated apoptosis and extension of the vector life span. Biological significanceRBSDV causes severe yield loss in rice plants. RBSDV is transmitted efficiently only through SBPH. It is important to understand how RBSDV infects SBPH in a persistent, circulative and propagative manner. However, there has been no study on the interaction between RBSDV and SBPH at the early acquisition stage using a proteomics approach. In this study, we combined iTRAQ technique and LC-MS/MS to analyze the vector proteomics at both the initial and latent infection stages after RBSDV acquisition and verified the results by RT-qPCR. Our results revealed that significantly low DAPs were involved in various pathways, including biosynthesis of secondary metabolites, ribosomes, carbon metabolism, biosynthesis of amino acids and TCA cycle. Further clustering of the DAPs revealed significant changes in SBPH mitochondria, including decreased proteins in mitochondrial ribosomes and electron transport chain complex I, II and V. On the other hand, there was a high abundance of Parkin, suggesting the occurrence of mitochondria damage and subsequent Parkin-mediated mitophagy for clearance of impaired mitochondria. Moreover, the decreased level of PMPCB in terms of gene expression and protein abundance suggested decreased PINK1 turnover, promoting Parkin/PINK1-mediated mitophagy. Further analysis on autophagy/mitophagy-related gene transcription level indicated up-regulation of OPTN, p62/SQSTM1, TAX1BP1 and TBK1, promoting selective autophagy in SBPH after RBSDV acquisition. These findings provided new insights into the effects of RBSDV on SBPH after early acquisition by selective degradation of mitochondria, especially on reprogramming of energy metabolism and decreased mitochondria biogenesis, to prevent apoptosis and prolong the life span of SBPH post virus acquisition.

Sarcoma Metabolomics: Current Horizons and Future Perspectives.

The vast array of metabolic adaptations that cancer cells are capable of assuming, not only support their biosynthetic activity, but also fulfill their bioenergetic demands and keep their intracellular reduction–oxidation (redox) balance. Spotlight has recently been placed on the energy metabolism reprogramming strategies employed by cancer cells to proliferate. Knowledge regarding soft tissue and bone sarcomas metabolome is relatively sparse. Further characterization of sarcoma metabolic landscape may pave the way for diagnostic refinement and new therapeutic target identification, with benefit to sarcoma patients. This review covers the state-of-the-art knowledge on cancer metabolomics and explores in detail the most recent evidence on soft tissue and bone sarcoma metabolomics.

Ceramide Synthase 6 Knockout Reprograms Energy Metabolism in Mice

Abstract Objectives Ceramides, a group of bioactive lipids and important signaling molecules, have been implicated in the development of cardiometabolic disease, diabetes, and cancer. Recent studies have shown that targeting Ceramide Synthases (CerS), the enzymes producing ceramides, protected from glucose intolerance and diet induced obesity. We investigated metabolomic responses to high fat diet consumption in livers and plasma of wild type (WT) and CerS6 knockout (KO) mice to obtain mechanistic understanding of the protection provided by the enzyme knockout. Methods Upon weaning, male WT and CerS6 KO mice were placed on a high fat (HFD) or control (Ctrl) diet for 16 weeks. After 14 weeks on diet, mice were placed in calorimetry cages for 48 hours. Body composition was assessed before dietary intervention and before necropsy. Plasma and snap-frozen liver samples were subjected to untargeted metabolomic analysis at Metabolon®. Results CerS6 KO mice gained significantly less weight on HFD than WT mice. Calorimetry measurements revealed that over 24 hours CerS6 KO mice did not move more than WT in either x-, y- or z-planes. Interestingly, CerS6 KO mice on a HFD consumed significantly less food, and despite the higher caloric content of the diet, they also consumed fewer calories over the 24 hour period. No differences in fat excretion between WT and CerS6 KO mice were found, measured by fecal lipid content. Calorimetry data demonstrated that on HFD, regardless of genotype, animals oxidized fat for energy. On the Ctrl diet WT mice burned a mix of substrates while CerS6 KO mice preferentially oxidized glucose for energy during the light cycle. This indicates that during the active phase of the light cycle a switch in energy source occurred in KO but not WT mice. Untargeted metabolomics revealed significant differences in intermediates of glycolysis both in liver and plasma of the KO vs WT animals. Moreover, significant increases in multiple TCA cycle metabolites in KO vs WT plasma were seen in HFD fed mice. Conclusions We found a significant shift in tissue-level and whole-body energetics in CerS6 KO mice. This shift could be responsible for the beneficial metabolic effects of targeting CerS6 when HFD is consumed. Further studies will help determine how CerS6 and ceramides influence tissue and whole body metabolism. Funding Sources This work was funded by R01 CA193782 grant to NK.

Effects of Guava (Psidium guajava L.) Leaf Extract on the Metabolomics of Serum and Feces in Weaned Piglets Challenged by Escherichia coli.

The effects of dietary supplementation with guava leaf extracts (GE) on intestinal barrier function and serum and fecal metabolome in weaned piglets challenged by enterotoxigenic Escherichia coli (ETEC) were investigated. In total, 50 weaned piglets (Duroc × Yorkshire × Landrace) from 25 pens (two piglets per pen) were randomly divided into five groups: BC (blank control), NC (negative control), S50 (supplemented with 50 mg kg−1 diet GE), S100 (100 mg kg−1 diet GE), and S200 (200 mg kg−1 diet GE), respectively. On day 4, all groups (except BC) were orally challenged with enterotoxigenic ETEC at a dose of 1.0 × 109 colony-forming units (CFUs). After treatment for 28 days, intestinal barrier function and parallel serum and fecal metabolomics analysis were carried out. Results suggested that dietary supplementation with GE (50–200 mg kg−1) increased protein expression of intestinal tight junction proteins (ZO-1, occludin, claudin-1) (p < 0.05) and Na+/H+ exchanger 3 (NHE3) (p < 0.05). Moreover, dietary supplementation with GE (50–200 mg kg−1) increased the level of tetrahydrofolic acid (THF) and reversed the higher level of nicotinamide-adenine dinucleotide phosphate (NADP) induced by ETEC in serum compared with the NC group (p < 0.05), and enhanced the antioxidant capacity of piglets. In addition, dietary addition with GE (100 mg kg−1) reversed the lower level of L-pipecolic acid induced by ETEC in feces compared with the NC group (p < 0.05) and decreased the oxidative stress of piglets. Collectively, dietary supplementation with GE exhibited a positive effect on improving intestinal barrier function. It can reprogram energy metabolism through similar or dissimilar metabolic pathways and finally enhance the antioxidant ability of piglets challenged by ETEC.

Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells.

Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.

SMYD2 suppresses p53 activity to promote glucose metabolism in cervical cancer

Reprogrammed energy metabolism, especially the Warburg effect, is emerged as a hallmark of cancer. The protein lysine methyltransferase SMYD2 functions as an oncogene and is implicated in various malignant phenotypes of human cancers. However, the role of SMYD2 in tumor metabolism is still largely unknown. Here, we report that SMYD2 is highly expressed in human cervical cancer and its aberrant expression is linked to a poor prognosis. Bioinformatic analysis revealed a novel link between SMYD2 expression and aerobic glycolysis. Through loss-of-function experiments, we demonstrated that SMYD2 knockdown or inhibition induced a metabolic shift from aerobic glycolysis to oxidative phosphorylation, as evidenced by glucose uptake, lactate production, extracellular acidification, and the oxygen consumption rate. In contrast, SMYD2 overexpression promoted glycolytic metabolism in cervical cancer cells. Moreover, SMYD2 was required for tumor growth in cervical cancer and this oncogenic activity was largely glycolysis-dependent. Mechanistically, SMYD2 altered the methylation status of p53 and inhibited its transcriptional activity. Genetic silencing of p53 largely abrogated the effects of SMYD2 in promoting aerobic glycolysis. Taken together, our findings reveal a novel function of SMYD2 in regulating the Warburg effect in cervical cancer.

KSHV Reprogramming of Host Energy Metabolism for Pathogenesis.

Reprogramming of energy metabolism is a key for cancer development. Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic herpesvirus, is tightly associated with several human malignancies by infecting B-lymphocyte or endothelial cells. Cancer cell energy metabolism is mainly dominated by three pathways of central carbon metabolism, including aerobic glycolysis, glutaminolysis, and fatty acid synthesis. Increasing evidence has shown that KSHV infection can alter central carbon metabolic pathways to produce biomass for viral replication, as well as the survival and proliferation of infected cells. In this review, we summarize recent studies exploring how KSHV manipulates host cell metabolism to promote viral pathogenesis, which provides the potential therapeutic targets and strategies for KSHV-associated cancers.

Octamer transcription factor-1 induces the Warburg effect via up-regulation of hexokinase 2 in non-small cell lung cancer

Reprogramming of energy metabolism is a hallmark of cancer which is prevalent worldwide. Octamer transcription factor-1 (OCT1) is a well-known transcription factor. However, the role of OCT1 in metabolism remodeling has not been well defined. In the present study, we found that OCT1 was up-regulated in non-small cell lung cancer (NSCLC) and correlated with poor patient survival. Further data identified that OCT1 increased glycolysis flux, promoting proliferation in lung cancer cells. Mechanistically, OCT1 facilitated the aerobic glycolysis and cell proliferation via up-regulation of hexokinase 2 (HK2), a crucial enzyme of the Warburg effect. Hence, our findings indicate that, in NSCLC, high levels of OCT1 contribute to the Warburg effect through up-regulation of HK2, linking up the OCT1/HK2 axis and cancer progression, which provide a potential biomarker and therapeutic target for NSCLC treatment.

The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks.

Simple SummaryPoly (ADP-ribose) polymerase (PARP) proteins regulate DNA damage correction, replication, and gene transcription. By controlling pivotal aspects of these processes, PARPs are heavily implicated in cancer development. Inhibitors of PARPs, approved for cancer chemotherapy a few years ago, have achieved great success against tumors of the breast and ovary carrying mutations in the BRCA1/2 genes. The spectrum of the inhibitors is avidly sought to be extended to tumors with different genetic backgrounds and cancers of other origins. This pursuit requires thorough apprehension of PARP-dependent processes affecting cancer development. The hallmarks of cancer are acquired by defining capabilities that differentiate cancer cells from their normal counterparts. Here, in two joint papers, we walk through the connections between these cancer traits and PARP functions. The present review focuses on how PARPs affect the features of cancer that can be attributed to cell-intrinsic changes increasing proliferative potential and survival capabilities. In a kindred paper, we explore the PARP association of cancer hallmarks that derive from tissue-level reorganization in tumors and intercellular interactions of cancer cells.The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

Metabolomics Analysis Reveals Deranged Energy Metabolism and Amino Acid Metabolic Reprogramming in Dogs With Myxomatous Mitral Valve Disease.

BackgroundMyxomatous mitral valve disease (MMVD), a naturally occurring heart disease, affects 10% to 15% of the canine population. Canine MMVD shares many similarities with human MMVD. Untargeted metabolomics was performed to identify changes in metabolic pathways and biomarkers with potential clinical utilities.Methods and ResultsSerum samples from 27 healthy, 22 stage B1, 18 stage B2 preclinical MMVD dogs, and 17 MMVD dogs with a history of congestive heart failure (CHF) were analyzed. Linear regression analysis identified 173 known metabolites whose concentrations were different among the 4 groups (adjusted P<0.05), of which 40% belonged to amino acid super pathways, while 30% were lipids. More than 50% of significant metabolites were correlated with left atrial diameter but not left ventricular dimension. Acylcarnitines, tricarboxylic acid cycle intermediates, and creatine accumulated in proportion to MMVD severity. α‐Ketobutyrate and ketone bodies were increased as MMVD advanced. Nicotinamide, a key substrate of the main nicotinamide adenine dinucleotide (NAD+) salvage pathway, was decreased, while quinolinate of the de novo NAD+ biosynthesis was increased in CHF dogs versus healthy dogs. 3‐Methylhistidine, marker for myofibrillar protein degradation, was higher in CHF dogs than non‐CHF dogs. Trimethylamine N‐oxide (TMAO) and TMAO–producing precursors, including carnitine, phosphatidylcholine, betaine, and trimethyllysine, were increased in CHF dogs versus non‐CHF dogs. Elevated levels of uremic toxins, including guanidino compounds, TMAO, and urea, were observed in CHF dogs. Pathway analysis highlighted the importance of bioenergetics and amino acid metabolism in canine MMVD.ConclusionsOur study revealed altered energy metabolism, amino acid metabolic programming, and reduced renal function in the development of MMVD and CHF. Complex interplays along the heart‐kidney‐gut axis were implicated.

Mitochondrial bioenergetic pathways in blood leukocyte transcriptome decrease after intensive weight loss but are rescued following weight regain in female physique athletes.

Prolonged periods of energy deficit leading to weight loss induce metabolic adaptations resulting in reduced energy expenditure, but the mechanisms for energy conservation are incompletely understood. We examined 42 healthy athletic females (age 27.5±4.0years, body mass index 23.4±1.7kg/m2 ) who volunteered into either a group dieting for physique competition (n=25) or a control group (n=17). The diet group substantially reduced their energy intake and moderately increased exercise levels to induce loss of fat mass that was regained during a voluntary weight regain period. The control group maintained their typical lifestyle habits and body mass as instructed. From the diet group, fasting blood samples were drawn at baseline (PRE), after 4- to 5-month weight loss (PRE-MID), and after 4- to 5-month weight regain (MID-POST) as well as from the control group at similar intervals. Blood was analyzed to determine leukocyte transcriptome by RNA-Sequencing and serum metabolome by nuclear magnetic resonance (NMR) platform. The intensive weight loss period induced several metabolic adaptations, including a prominent suppression of transcriptomic signature for mitochondrial OXPHOS and ribosome biogenesis. The upstream regulator analysis suggested that this reprogramming of cellular energy metabolism may be mediated via AMPK/PGC1-α signaling and mTOR/eIF2 signaling-dependent pathways. Our findings show for the first time that prolonged energy deprivation induced modulation of mitochondrial metabolism can be observed through minimally invasive measures of leukocyte transcriptome and serum metabolome at systemic level, suggesting that adaptation to energy deficit is broader in humans than previously thought.

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing.

Simple SummarySome regions of aggressive malignancies experience hypoxia due to inadequate blood supply. Cancer cells adapting to hypoxic conditions somehow become more resistant to radiation exposure and this decreases the efficacy of radiotherapy toward hypoxic tumors. The present review article helps clarify two intriguing points: why hypoxia-adapted cancer cells turn out radioresistant and how they can be rendered more radiosensitive. The critical molecular targets associated with intratumoral hypoxia and various approaches are here discussed which may be used for sensitizing hypoxic tumors to radiotherapy.Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.