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MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation.
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sánchez V, Sanders ME, Lee T, Gómez H, Lluch A, Pérez-Fidalgo JA, Wolf MM, Andrejeva G, Rathmell JC, Fesik SW, Arteaga CL
(2017) Cell Metab 26: 633-647.e7
MeSH Terms: Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Mice, Nude, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplastic Stem Cells, Oxidative Phosphorylation, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
Copyright © 2017. Published by Elsevier Inc.
0 Communities
1 Members
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13 MeSH Terms
Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.
Feichtinger RG, Neureiter D, Skaria T, Wessler S, Cover TL, Mayr JA, Zimmermann FA, Posselt G, Sperl W, Kofler B
(2017) Oxid Med Cell Longev 2017: 1320241
MeSH Terms: Electron Transport Complex I, Female, Gastritis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Helicobacter Infections, Helicobacter pylori, Humans, Male, Neoplasm Proteins, Oxidative Phosphorylation, Stomach Neoplasms
Show Abstract · Added March 21, 2018
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
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12 MeSH Terms
Defining a Novel Role for the Pdx1 Transcription Factor in Islet β-Cell Maturation and Proliferation During Weaning.
Spaeth JM, Gupte M, Perelis M, Yang YP, Cyphert H, Guo S, Liu JH, Guo M, Bass J, Magnuson MA, Wright C, Stein R
(2017) Diabetes 66: 2830-2839
MeSH Terms: Animals, Cell Proliferation, Gene Expression Regulation, Homeodomain Proteins, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Oxidative Phosphorylation, Trans-Activators, Weaning
Show Abstract · Added August 1, 2017
The transcription factor encoded by the gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β-cell development, and adult islet β-cell function. Transgenic- and cell line-based experiments have identified 5'-flanking conserved sequences that control pancreatic and β-cell type-specific transcription, which are found within areas I (bp -2694 to -2561), II (bp -2139 to -1958), III (bp -1879 to -1799), and IV (bp -6200 to -5670). Because of the presence in area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected expression embryonically and postnatally. The most striking result was observed in male mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β-cells were tightly linked with hyperglycemia, decreased β-cell proliferation, reduced β-cell area, and altered expression of Pdx1-bound genes that are important in β-cell replication, endoplasmic reticulum function, and mitochondrial activity. We discuss the impact of these novel findings to gene regulation and islet β-cell maturation postnatally.
© 2017 by the American Diabetes Association.
3 Communities
2 Members
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11 MeSH Terms
Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers.
Lark DS, Torres MJ, Lin CT, Ryan TE, Anderson EJ, Neufer PD
(2016) Am J Physiol Cell Physiol 311: C239-45
MeSH Terms: Adenosine Diphosphate, Adenosine Triphosphate, Adenylate Kinase, Animals, Glucosephosphate Dehydrogenase, Hexokinase, Male, Mice, Mice, Inbred C57BL, Mitochondria, Muscle Fibers, Skeletal, NADP, Oxidative Phosphorylation, Oxygen Consumption
Show Abstract · Added October 17, 2016
Oxidative phosphorylation (OXPHOS) efficiency, defined as the ATP-to-O ratio, is a critical feature of mitochondrial function that has been implicated in health, aging, and disease. To date, however, the methods to measure ATP/O have primarily relied on indirect approaches or entail parallel rather than simultaneous determination of ATP synthesis and O2 consumption rates. The purpose of this project was to develop and validate an approach to determine the ATP/O ratio in permeabilized fiber bundles (PmFBs) from simultaneous measures of ATP synthesis (JATP) and O2 consumption (JO2 ) rates in real time using a custom-designed apparatus. JO2 was measured via a polarigraphic oxygen sensor and JATP via fluorescence using an enzyme-linked assay system (hexokinase II, glucose-6-phosphate dehydrogenase) linked to NADPH production. Within the dynamic linear range of the assay system, ADP-stimulated increases in steady-state JATP mirrored increases in steady-state JO2 (r(2) = 0.91, P < 0.0001, n = 57 data points). ATP/O ratio was less than one under low rates of respiration (15 μM ADP) but increased to more than two at moderate (200 μM ADP) and maximal (2,000 μM ADP) rates of respiration with an interassay coefficient of variation of 24.03, 16.72, and 11.99%, respectively. Absolute and relative (to mechanistic) ATP/O ratios were lower in PmFBs (2.09 ± 0.251, 84%) compared with isolated mitochondria (2.44 ± 0.124, 98%). ATP/O ratios in PmFBs were not affected by the activity of adenylate kinase or creatine kinase. These findings validate an enzyme-linked respiratory clamp system for measuring OXPHOS efficiency in PmFBs and provide evidence that OXPHOS efficiency increases as energy demand increases.
Copyright © 2016 the American Physiological Society.
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14 MeSH Terms
HIF1α and HIF2α exert distinct nutrient preferences in renal cells.
Arreola A, Cowey CL, Coloff JL, Rathmell JC, Rathmell WK
(2014) PLoS One 9: e98705
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Carbon, Cell Line, Culture Media, Epithelial Cells, Food, Gene Expression, Glucose, Glutamic Acid, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Metabolome, Mice, Oxidative Phosphorylation, Transcription Factors
Show Abstract · Added October 17, 2015
BACKGROUND - Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells.
METHODS - We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene.
RESULTS - Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media.
CONCLUSION - HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients.
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16 MeSH Terms
5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo.
Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH
(2014) J Biol Chem 289: 5950-9
MeSH Terms: AMP-Activated Protein Kinases, Aminoimidazole Carboxamide, Animals, Energy Metabolism, Fatty Acids, Glucose, Hypoglycemic Agents, Liver, Mice, Mice, Knockout, Mitochondria, Liver, Oxidative Phosphorylation, Ribonucleotides, Triglycerides
Show Abstract · Added April 17, 2014
Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; 8 mg·kg(-1)·min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (α1α2(lox/lox)) and liver-specific AMPK knock-out mice (α1α2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted α1α2(lox/lox) and α1α2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by ∼20% in α1α2(lox/lox), which was exacerbated by ∼2-fold in α1α2(lox/lox) + Albcre. This corresponded to a ∼6-fold rise in AMP/ATP in α1α2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ∼30% lower in α1α2(lox/lox) + Albcre than α1α2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration.
1 Communities
2 Members
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14 MeSH Terms
Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA
(2013) Cell 155: 1624-38
MeSH Terms: AMP-Activated Protein Kinases, Aging, Animals, Cell Nucleus, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mitochondria, Muscle, Skeletal, NAD, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Reactive Oxygen Species, Sirtuin 1, Transcription Factors
Show Abstract · Added March 4, 2015
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
Copyright © 2013 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Mesenchymal stem cell transplantation for the infarcted heart: therapeutic potential for insulin resistance beyond the heart.
Hughey CC, Ma L, James FD, Bracy DP, Wang Z, Wasserman DH, Rottman JN, Hittel DS, Shearer J
(2013) Cardiovasc Diabetol 12: 128
MeSH Terms: Adipose Tissue, Animals, Blood Glucose, Cells, Cultured, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Fatty Acids, Glucose Transporter Type 4, Humans, Insulin, Insulin Resistance, Male, Mesenchymal Stem Cell Transplantation, Mice, Mice, Inbred C57BL, Mitochondria, Heart, Muscle, Skeletal, Myocardial Infarction, Myocardium, Oxidative Phosphorylation, Phosphorylation, Proto-Oncogene Proteins c-akt, Recovery of Function, Stroke Volume, Systole, Time Factors
Show Abstract · Added April 17, 2014
BACKGROUND - This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance.
METHODS - C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers.
RESULTS - MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding.
CONCLUSIONS - These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.
2 Communities
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27 MeSH Terms
Metabolic flux rewiring in mammalian cell cultures.
Young JD
(2013) Curr Opin Biotechnol 24: 1108-15
MeSH Terms: Animals, Cell Culture Techniques, Cells, Glucose, Glutamine, Glycolysis, Humans, Lactic Acid, Metabolic Engineering, Metabolic Flux Analysis, Oxidative Phosphorylation
Show Abstract · Added January 23, 2015
Continuous cell lines (CCLs) engage in 'wasteful' glucose and glutamine metabolism that leads to accumulation of inhibitory byproducts, primarily lactate and ammonium. Advances in techniques for mapping intracellular carbon fluxes and profiling global changes in enzyme expression have led to a deeper understanding of the molecular drivers underlying these metabolic alterations. However, recent studies have revealed that CCLs are not necessarily entrenched in a glycolytic or glutaminolytic phenotype, but instead can shift their metabolism toward increased oxidative metabolism as nutrients become depleted and/or growth rate slows. Progress to understand dynamic flux regulation in CCLs has enabled the development of novel strategies to force cultures into desirable metabolic phenotypes, by combining fed-batch feeding strategies with direct metabolic engineering of host cells.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Enhanced cardiac protein glycosylation (O-GlcNAc) of selected mitochondrial proteins in rats artificially selected for low running capacity.
Johnsen VL, Belke DD, Hughey CC, Hittel DS, Hepple RT, Koch LG, Britton SL, Shearer J
(2013) Physiol Genomics 45: 17-25
MeSH Terms: Absorptiometry, Photon, Analysis of Variance, Animals, Carbon Radioisotopes, Citrate (si)-Synthase, Fatty Acids, Nonesterified, Glucose, Glucose Clamp Technique, Glycosylation, Immunoblotting, Insulin Resistance, Kinetics, Mitochondrial Proteins, Models, Animal, Myocardium, N-Acetylglucosaminyltransferases, Oxidative Phosphorylation, Rats, Rats, Inbred Strains, Running
Show Abstract · Added April 24, 2014
O-linked β-N-acetyl glucosamine (O-GlcNAc) is a posttranslational modification consisting of a single N-acetylglucosamine moiety attached by an O-β-glycosidic linkage to serine and threonine residues of both nuclear and cytosolic proteins. Analogous to phosphorylation, the modification is reversible and dynamic, changing in response to stress, nutrients, hormones, and exercise. Aims of this study were to examine differences in O-GlcNAc protein modification in the cardiac tissue of rats artificially selected for low (LCR) or high (HCR) running capacity. Hyperinsulinemic-euglycemic clamps in conscious animals assessed insulin sensitivity while 2-[(14)C] deoxyglucose tracked both whole body and tissue-specific glucose disposal. Immunoblots of cardiac muscle examined global O-GlcNAc modification, enzymes that control its regulation (OGT, OGA), and specific proteins involved in mitochondrial oxidative phosphorylation. LCR rats were insulin resistant disposing of 65% less glucose than HCR. Global tissue O-GlcNAc, OGT, OGA, and citrate synthase were similar between groups. Analysis of cardiac proteins revealed enhanced O-GlcNAcylation of mitochondrial Complex I, Complex IV, VDAC, and SERCA in LCR compared with HCR. These results are the first to establish an increase in specific protein O-GlcNAcylation in LCR animals that may contribute to progressive mitochondrial dysfunction and the pathogenesis of insulin resistance observed in the LCR phenotype.
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20 MeSH Terms