Abstract 3866: The KISS1 metastasis suppressor appears to reverse the Warburg effect by enhancing mitochondria biogenesis.
Wen LiuBenjamin H. BeckKedar S. VaidyaKevin T. NashAnne R. DiersKyle P. FeeleyAimee LandarScott W. BallingerDanny R. Welch
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Abstract Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, which is commonly called the “Warburg Effect.” Aerobic glycolysis often directly correlates with malignant potential. Though its purpose remains unclear, the “Warburg Effect” is thought to confer advantages to proliferation, survival and dissemination to cancer cells by increasing uptake of nutrients into biomass. KISS1 protein is secreted and proteolytically cleaved into kisspeptins (KP) that block the colonization of disseminated metastatic C8161.9 human melanoma cells at secondary sites. In this study, we hypothesized that KISS1 metastasis suppression occurs via regulation of aerobic glycolysis. Comparison of bioenergetic and metabolic aspects of glucose metabolism showed that all KISS1-secreting clones were less invasive, took up less glucose, produced less lactate which corresponds to higher pH[Ex], effects which were reversed when cells were transduced with shRNA to KISS1. The metabolism, invasion, and metastasis changes did not occur when KISS1 was missing the signal peptide (ΔSS). Utilizing a Seahorse bioanalyzer, KISS1, but not ΔSS cells showed significantly decreased extracellular acidification rates, increased O2 consumption and elevated mitochondria reserve capacity, an indicator of mitochondrial condition and a parameter thought to improve the cells’ ability to cope with oxidative stress. KISS1-expressing cells have 30-50% more mitochondria compared to vector or ΔSS-expressing cells. Increased mitochondrial mass was accompanied by significantly increased expression of mitochondrial genes involved in apoptosis and mitophagy, protein processing and trafficking. Increased mitochondrial mass correlated with higher PGC1α considered to be a master co-activator that regulates mitochondrial mass and metabolism. Interestingly, KISS1 differentially affects PGC1α-mediated downstream pathways, i.e. fatty acid synthesis and β-oxidation. KISS1-mediated up-regulation of mitochondria biogenesis appears to rely on KISS1 interaction with NRF1, a major transcription factor of mitochondria biogenesis. KP10 (which can activate the KISS1 receptor) does not alter pH[Ex] since the metastatic tumor cells do not express KISS1R. This paradox - metastasis and metabolic changes require secretion, but responding cells do not have the receptor - raises questions regarding the mechanism. Nonetheless, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis. [Support: CA134581, Natl. Fndn. Cancer Res., Komen SAC110037]. Citation Format: Wen Liu, Benjamin H. Beck, Kedar S. Vaidya, Kevin T. Nash, Anne R. Diers, Kyle P. Feeley, Aimee Landar, Scott W. Ballinger, Danny R. Welch. The KISS1 metastasis suppressor appears to reverse the Warburg effect by enhancing mitochondria biogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3866. doi:10.1158/1538-7445.AM2013-3866Keywords:
Warburg Effect
Anaerobic glycolysis
Bioenergetics
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.
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While transformation of normal cells to cancer cells is accompanied with a switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, it is interesting to ask if cancer cells can revert from Warburg effect to OXPHOS. Our previous works suggested that cancer cells reverted to OXPHOS, when they were exposed to lactic acidosis, a common factor in tumor environment. However, the conclusion cannot be drawn unless ATP output from glycolysis and OXPHOS is quantitatively determined. Here we quantitatively measured ATP generation from glycolysis and OXPHOS in 9 randomly selected cancer cell lines. Without lactic acidosis, glycolysis and OXPHOS generated 23.7% - 52.2 % and 47.8% - 76.3% of total ATP, respectively; with lactic acidosis (20 mM lactate with pH 6.7), glycolysis and OXPHOS provided 5.7% - 13.4% and 86.6% - 94.3% of total ATP. We concluded that cancer cells under lactic acidosis reverted from Warburg effect to OXPHOS phenotype.
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Warburg Effect
Anaerobic glycolysis
Carbohydrate Metabolism
Cellular respiration
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The Warburg effect, a switch from aerobic energy production to anaerobic glycolysis, promotes tumour proliferation and motility by inducing acidification of the tumour microenvironment. Therapies that reduce acidity could impair tumour growth and invasiveness. I analysed the dynamics of cell proliferation and of resistance to therapies that target acidity, in a population of cells, under the Warburg effect.The dynamics of mutant cells with increased glycolysis and motility has been assessed in a multi-player game with collective interactions in the framework of evolutionary game theory. Perturbations of the level of acidity in the microenvironment have been used to simulate the effect of therapies that target glycolysis.The non-linear effects of glycolysis induce frequency-dependent clonal selection leading to coexistence of glycolytic and non-glycolytic cells within a tumour. Mutants with increased motility can invade such a polymorphic population and spread within the tumour. While reducing acidity may produce a sudden reduction in tumour cell proliferation, frequency-dependent selection enables it to adapt to the new conditions and can enable the tumour to restore its original levels of growth and invasiveness.The acidity produced by glycolysis acts as a non-linear public good that leads to coexistence of cells with high and low glycolysis within the tumour. Such a heterogeneous population can easily adapt to changes in acidity. Therapies that target acidity can only be effective in the long term if the cost of glycolysis is high, that is, under non-limiting oxygen concentrations. Their efficacy, therefore, is reduced when combined with therapies that impair angiogenesis.
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Warburg Effect
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Activated oncogenes and loss of tumor suppressors contribute to reprogrammed energy metabolism and induce aerobic glycolysis, also known as Warburg effect. MicroRNAs are profoundly implicated in human malignancies by inhibiting translation of multiple mRNA targets. Using hepatocellular carcinoma (HCC) molecular profiles from The Cancer Genome Atlas (TCGA), we identified a handful of dysregulated microRNA in HCC glycolysis, especially miR-34c-3p. Antagonization of miR-34c-3p inhibited the lactate production, glucose consumption, extracellular acidification rate (ECAR), and aggressive proliferation in HCC cells. Hijacking glycolysis by 2-deoxy-d-glucose or galactose largely abrogated the suppressive effects of miR-34c-3p inhibition in HCC. Membrane associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) is then identified as a direct functional target of miR-34c-3p in regulating HCC glycolysis and oncogenic activities. Mechanistically, MAGI3 physically interacted with β-catenin to regulate its transcriptional activity and c-Myc expression, which further facilitates the Warburg effect by increasing expression of glycolytic genes including HK2, PFKL, and LDHA. Moreover, overexpressed miR-34c-3p and reduced MAGI3 predicted poor clinical outcome and was closely associated with the maximum standard uptake value (SUVmax) in HCC patients who received preoperative 18F-FDG PET/CT. Our findings elucidate critical several microRNAs implicated in HCC glycolysis and reveal a novel function of miR-34c-3p/MAGI3 axis in Warburg effect through regulating β-catenin activity.
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A Low Carbohydrate, High Protein Diet May Extend Your Life and Reduce Your Chances of Getting Cancer
When glucose in our blood enters our cells it is broken down via glycolysis to pyruvate. Pyruvate can then be converted to lactic acid and secreted, ending glycolysis, or into acetyl-CoA and broken down, with the help of oxygen (O 2 ), within mitochondria to carbon dioxide (CO 2 ) and water via oxidative phosphorylation (OXPHOS, i.e., the Kreb’s, Citric acid or tricarboxylic acid cycle) 1 . In 1857 Louis Pasteur discovered that in the absence of O 2 , normal cells survive by switching from OXPHOS, which generates 36 ATPs/glucose, to glycolysis, which only generates 2 ATPs/glucose. In the 1920s, Otto Warburg found that cancer (CA) cells, unlike normal cells, use glycolysis instead of OXPHOS even when O 2 is present, and this is called “aerobic glycolysis” or the ‘Warburg effect’ 1 . Because most tumours use this less efficient energy generating system, they have to take up more blood glucose (BG) than normal cells to survive and this is the basis for identifying human CAs using PET scans with the glucose analog, 18 fluorodeoxyglucose 2
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Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the reverse Warburg effect. Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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Aerobic glycolysis, i.e. , the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma.However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells.To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e. , the "reverse Warburg effect".Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment.This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent.Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
Warburg Effect
Anaerobic glycolysis
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