Loss of the Mitochondrial Bioenergetic Capacity Underlies the Glucose Avidity of Carcinomas (original) (raw)
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The bioenergetics of cancer: Is glycolysis the main ATP supplier in all tumor cells?
BioFactors, 2009
The molecular mechanisms by which tumor cells achieve an enhanced glycolytic flux and, presumably, a decreased oxidative phosphorylation are analyzed. As the O 2 concentration in hypoxic regions of tumors seems not limiting for oxidative phosphorylation, the role of this mitochondrial pathway in the ATP supply is re-evaluated. Drugs that inhibit glycoysis and oxidative phosphorylation are analyzed for their specificity toward tumor cells and effect on proliferation. The energy metabolism mechanisms involved in the use of positron emission tomography are revised and updated. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.
International Journal of Molecular Sciences, 2012
Warburg's hypothesis has been challenged by a number of studies showing that oxidative phosphorylation is repressed in some tumors, rather than being inactive per se. Thus, treatments able to shift energy metabolism by activating mitochondrial pathways have been suggested as an intriguing basis for the optimization of antitumor strategies. In this study, HepG2 hepatocarcinoma cells were cultivated with different metabolic substrates under conditions mimicking -positive‖ (activation/biogenesis) or -negative‖ (silencing) mitochondrial adaptation. In addition to the expected up-regulation of mitochondrial biogenesis, glucose deprivation caused an increase in phosphorylating respiration and a rise in the expression levels of the ATP synthase β subunit and Inhibitor Factor 1 (IF1). Hyperglycemia, on the other hand, led to a markedly decreased level of the transcriptional coactivator PGC-α suggesting down-regulation of mitochondrial biogenesis, although no change in mitochondrial mass and no impairment of phosphorylating respiration were observed. Moreover, a reduction in mitochondrial networking and in ATP synthase dimer stability was produced. No effect on β-ATP synthase expression was elicited. Notably, hyperglycemia caused an increase in IF1 expression levels, but it did not alter the amount of IF1 associated with ATP synthase. These results point to a new role of IF1 in relation to high glucose utilization by tumor cells, in addition to its well known effect upon mitochondrial ATP synthase regulation.
Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ
Cell Cycle, 2011
We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cancer cells behave as metabolic parasites, by extracting nutrients from normal host cells, such as fibroblasts, via the secretion of hydrogen peroxide as the initial trigger. oxidative stress in the tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function and aerobic glycolysis. this, in turn, produces high-energy nutrients (such as L-lactate, ketones and glutamine) that drive the anabolic growth of tumor cells, via oxidative mitochondrial metabolism. a logical prediction of this new "parasitic" cancer model is that tumor-associated fibroblasts should show evidence of mitochondrial dys-function (mitophagy and aerobic glycolysis). In contrast, epithelial cancer cells should increase their oxidative mitochondrial capacity. to further test this hypothesis, here we subjected frozen sections from human breast tumors to a staining procedure that only detects functional mitochondria. this method detects the in situ enzymatic activity of cytochrome C oxidase (CoX), also known as Complex IV. Remarkably, cancer cells show an overabundance of CoX activity, while adjacent stromal cells remain essentially negative. adjacent normal ductal epithelial cells also show little or no CoX activity, relative to epithelial cancer cells. thus, oxidative mitochondrial activity is selectively amplified in cancer cells. although CoX activity staining has never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. similar results were obtained with NaDh activity staining, which measures Complex I activity, and succinate dehydrogenase (sDh) activity staining, which measures Complex II activity. CoX and NaDh activities were blocked by electron transport inhibitors, such as Metformin. this has mechanistic and clinical implications for using Metformin as an anti-cancer drug, both for cancer therapy and chemo-prevention. We also immuno-stained human breast cancers for a series of well-established protein biomarkers of metabolism. More specifically, we now show that cancer-associated fibroblasts overexpress markers of autophagy (cathepsin B), mitophagy (BNIp3L) and aerobic glycolysis (MCt4). Conversely, epithelial cancer cells show the overexpression of a mitochondrial membrane marker (toMM20), as well as key components of Complex IV (Mt-Co1) and Complex II (sDh-B). We also validated our observations using a bioinformatics approach with data from >2,000 breast cancer patients, which showed the transcriptional upregulation of mitochondrial oxidative phosphorylation (oXphos) in human breast tumors (p < 10-20), and a specific association with metastasis. therefore, upregulation of oXphos in epithelial tumor cells is a common feature of human breast cancers. In summary, our data provide the first functional in vivo evidence that epithelial cancer cells perform enhanced mitochondrial oxidative phosphorylation, allowing them to produce high amounts of atp. thus, we believe that mitochondria are both the "powerhouse" and "achilles' heel" of cancer cells.
International Journal of Cancer, 2008
The hypoxia-responsiveness of the glycolytic machinery may allow pretreatment identification of hypoxic tumors from HIF-1 targets (e.g., Glut-1) or [18F]-fluorodeoxyglucose positron emission tomography but results have been mixed. We hypothesized that this discrepancy is an inevitable consequence of elevated aerobic glycolysis in tumors (Warburg effect) as energetics in predominantly glycolytic cells is little affected by hypoxia. Accordingly, we characterized glycolytic and mitochondrial ATP generation in normoxic and anoxic cell lines. Measurements demonstrated that most cancer cells rely largely on aerobic glycolysis as it accounts for 56-63% of their ATP budget, but in the cervical carcinoma SiHa, ATP synthesis was mainly mitochondrial. Moreover, the stimulatory effect of anoxia on glycolytic flux was inversely correlated to the relative reliance on aerobic glycolysis. Next, tumor cells representing a Warburg or a nonglycolytic phenotype were grown in mice and spatial patterns of hypoxia (pimonidazolestained), Glut-1 expression and 18 F-FDG uptake were analysed on sectioned tumors. Only in SiHa tumors did foci of elevated glucose metabolism consistently colocalize with regions of hypoxia and elevated Glut-1 expression. In contrast, spatial patterns of Glut-1 and pimonidazole staining correlated reasonably well in all tumors. In conclusion, Glut-1's value as a hypoxia marker is not severely restricted by aerobic glycolysis. In contrast, the specificity of 18 F-FDG uptake and Glut-1 expression as markers of regional hypoxia and glucose metabolism, respectively, scales inversely with the intensity of the Warburg effect. This linkage suggests that multi-tracer imaging combining FDG and hypoxia-specific markers may provide therapeutically relevant information on tumor energetic phenotypes.
Mapping the Metabolic Landscape of Lung Adenocarcinoma: From Energy Flexibility in Early Stages to Glycolytic Entrapment in Advanced Disease, 2024
Lung adenocarcinoma, a subtype of non-small cell lung cancer (NSCLC), exhibits profound metabolic reprogramming as it progresses, characterized by a shift from oxidative phosphorylation (OXPHOS) to glycolysis, even in the presence of oxygen. This phenomenon, known as the Warburg effect, enables cancer cells to meet their increased energy and biosynthetic demands, facilitating rapid proliferation and tumor progression. In this study, we compared the metabolic profiles of 150 patients, including 75 with stage 4 lung adenocarcinoma and 75 with early-stage disease (stage I and II), to investigate the dynamic metabolic changes occurring as the disease advances. We analyzed key glycolysis markers-glucose, lactate, and pyruvate-along with oxidative phosphorylation markers-β-hydroxybutyrate, acetoacetate, glutamine, and alanine. The findings revealed a significant increase in glycolysis markers in the stage 4 group, indicating a pronounced shift towards glycolysis. Concurrently, oxidative phosphorylation markers showed a marked reduction, reflecting mitochondrial dysfunction. Additionally, inflammatory cytokines (IL-6, IL-1Beta, TNF-alpha) and lactate dehydrogenase (LDH) were elevated in the advanced-stage patients, contributing to the pro-tumorigenic environment and promoting immune evasion and angiogenesis. Oxidative stress markers, such as melatonin and dopamine, were significantly reduced in stage 4 patients, further underscoring the role of oxidative stress in disease progression. The metabolic reprogramming in lung adenocarcinoma is tightly linked to the tumor microenvironment, supporting immune evasion and metastatic potential. These findings highlight the critical metabolic changes in advanced lung adenocarcinoma and underscore the potential for targeting glycolysis and related pathways as therapeutic strategies. The decline in oxidative phosphorylation and the increase in glycolysis markers suggest a metabolic threshold beyond which traditional anticancer treatments may offer diminishing returns, necessitating novel interventions to disrupt tumor metabolism and improve patient outcomes. Highlights • Metabolic Shift to Glycolysis: Lung adenocarcinoma cells demonstrate a significant shift from oxidative phosphorylation to glycolysis (Warburg effect), especially in advanced stages, allowing cancer cells to meet the increased energy and biosynthetic demands of rapid tumor growth. • Increased Glycolysis Markers: Elevated levels of glycolysis markers such as glucose, lactate, and pyruvate were observed in stage 4 lung adenocarcinoma patients, indicating reliance on glycolysis for energy production. • Inflammatory Cytokine Elevation: Advanced-stage lung adenocarcinoma patients exhibited higher levels of
Cancer abolishes the tissue type-specific differences in the phenotype of energetic metabolism
Translational …, 2009
Nowadays, cellular bioenergetics has become a central issue of investigation in cancer biology. Recently, the metabolic activity of the cancer cell has been shown to correlate with a proteomic index that informs of the relative mitochondrial activity of the cell. Within this new field of investigation, we report herein the production and characterization of high-affinity monoclonal antibodies against proteins of the “bioenergetic signature” of the cell. The use of recombinant proteins and antibodies against the mitochondrial β-F1-ATPase and Hsp60 proteins and the enzymes of the glycolytic pathway glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase M2 in quantitative assays provide, for the first time, the actual amount of these proteins in normal and tumor surgical specimens of breast, lung, and esophagus. The application of this methodology affords a straightforward proteomic signature that quantifies the variable energetic demand of human tissues. Furthermore, the results show an unanticipated finding: tumors from different tissues and/or histological types have the same proteomic signature of energetic metabolism. Therefore, the results indicate that cancer abolishes the tissue-specific differences in the bioenergetic phenotype of mitochondria. Overall, the results support that energetic metabolism represents an additional hallmark of the phenotype of the cancer cell and a promising target for the treatment of diverse neoplasias.
Journal of Biological Chemistry, 2010
The H ؉-ATP synthase is a reversible engine of mitochondria that synthesizes or hydrolyzes ATP upon changes in cell physiology. ATP synthase dysfunction is involved in the onset and progression of diverse human pathologies. During ischemia, the ATP hydrolytic activity of the enzyme is inhibited by the ATPase inhibitory factor 1 (IF1). The expression of IF1 in human tissues and its participation in the development of human pathology are unknown. Here, we have developed monoclonal antibodies against human IF1 and determined its expression in paired normal and tumor biopsies of human carcinomas. We show that the relative mitochondrial content of IF1 increases significantly in carcinomas, suggesting the participation of IF1 in oncogenesis. The expression of IF1 varies significantly in cancer cell lines. To investigate the functional activity of IF1 in cancer, we have manipulated its cellular content. Overexpression of IF1 or of its pH-insensitive H49K mutant in cells that express low levels of IF1 triggers the up-regulation of aerobic glycolysis and the inhibition of oxidative phosphorylation with concurrent mitochondrial hyperpolarization. Treatment of the cells with the H ؉-ATP synthase inhibitor oligomycin mimicked the effects of IF1 overexpression. Conversely, small interfering RNA-mediated silencing of IF1 in cells that express high levels of IF1 promotes the down-regulation of aerobic glycolysis and the increase in oxidative phosphorylation. Overall, these findings support that the mitochondrial content of IF1 controls the activity of oxidative phosphorylation mediating the shift of cancer cells to an enhanced aerobic glycolysis, thus supporting an oncogenic role for the de-regulated expression of IF1 in cancer.
Analytical Determination of Mitochondrial Function of Excised Solid Tumor Homogenates
Journal of Visualized Experiments
Mitochondria are essential to the onset and progression of cancer through energy production, reactive oxygen species regulation, and macromolecule synthesis. Genetic and functional adaptations of mitochondria to the tumor environment drive proliferative and metastatic potential. The advent of DNA and RNA sequencing removed critical barriers to the evaluation of genetic mediators of tumorigenesis. However, to date, methodological approaches to evaluate tumor mitochondrial function remain elusive and require technical proficiency limiting the feasibility, ultimately diminishing diagnostic and prognostic value in both experimental and clinical settings. Here, we outline a simple and rapid method to quantify rates of oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity in freshly excised solid tumor homogenates using high-resolution respirometry. The protocol can be reproducibly applied across species and tumor types as well as adapted to evaluate a diversity of mitochondrial ET pathways. Using this protocol, we demonstrate that mice bearing a luminal B mammary cancer exhibit defective nicotinamide adenine dinucleotide-linked respiration and reliance on succinate to generate adenosine triphosphate via OXPHOS. often phenotypically distinguishable from non-cancerous tissue 1 , 2 , 3. As such, there is a critical need for rapid and deep profiling of mitochondrial respiratory function in order to faciliate the classification of tumor type, cancer initiation, progression, and treatment response. Respiratory functions of excised tissue specimens cannot be evaluated intact as the primary substrates for OXPHOS are not cell-permeable. To overcome this
Cell Metabolism, 2012
Dysregulated metabolism is a hallmark of cancer cell lines, but little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. To study tumor metabolism in vivo, we used an orthotopic mouse model of primary human glioblastoma (GBM). We infused 13 C-labeled nutrients into mice bearing three independent GBM lines, each with a distinct set of mutations. All three lines displayed glycolysis, as expected for aggressive tumors. They also displayed unexpected metabolic complexity, oxidizing glucose via pyruvate dehydrogenase and the citric acid cycle, and using glucose to supply anaplerosis and other biosynthetic activities. Comparing the tumors to surrounding brain revealed obvious metabolic differences, notably the accumulation of a large glutamine pool within the tumors. Many of these same activities were conserved in cells cultured ex vivo from the tumors. Thus GBM cells utilize mitochondrial glucose oxidation during aggressive tumor growth in vivo.
The tumor suppressor function of mitochondria: Translation into the clinics
Biochimica Et Biophysica Acta-molecular Basis of Disease, 2009
Recently, the inevitable metabolic reprogramming experienced by cancer cells as a result of the onset of cellular proliferation has been added to the list of hallmarks of the cancer cell phenotype. Proliferation is bound to the synchronous fluctuation of cycles of an increased glycolysis concurrent with a restrained oxidative phosphorylation.