The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

Liang, Weifa

doi:10.3892/ijmm.2010.579

Cited by 13 publications

(12 citation statements)

References 108 publications

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“…Whereas the origins of, and the mechanisms by which, cellular heterogeneity contributes unequally to tumorigenesis are unclear [51], it has been know for some time that the population average Δψm of cancer cells is significantly higher than that of normal cells ([24], [52]–[55] and that mitochondria are important and critical elements in establishing tumorigenic phenotype [56].…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

2011

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We have established previously that minor subpopulations of cells with stable differences in their intrinsic mitochondrial membrane potential (Δψm) exist within populations of mammary and colonic carcinoma cells and that these differences in Δψm are linked to tumorigenic phenotypes consistent with increased probability of participating in tumor progression. However, the mechanism(s) involved in generating and maintaining stable differences in intrinsic Δψm and how they are linked to phenotype are unclear. Because the mucin 1 (MUC1) oncoprotein is over-expressed in many cancers, with the cytoplasmic C-terminal fragment (MUC1 C-ter) and its integration into the outer mitochondrial membrane linked to tumorigenic phenotypes similar to those of cells with elevated intrinsic Δψm, we investigated whether endogenous differences in MUC1 levels were linked to stable differences in intrinsic Δψm and/or to the tumor phenotypes associated with the intrinsic Δψm. We report that levels of MUC1 are significantly higher in subpopulations of cells with elevated intrinsic Δψm derived from both mammary and colonic carcinoma cell lines. However, using siRNA we found that down-regulation of MUC1 failed to significantly affect either the intrinsic Δψm or the tumor phenotypes associated with increased intrinsic Δψm. Moreover, whereas pharmacologically mediated disruption of the Δψm was accompanied by attenuation of tumor phenotype, it had no impact on MUC1 levels. Therefore, while MUC1 over-expression is associated with subpopulations of cells with elevated intrinsic Δψm, it is not directly linked to the generation or maintenance of stable alterations in intrinsic Δψm, or to intrinsic Δψm associated tumor phenotypes. Since the Δψm is the focus of chemotherapeutic strategies, these data have important clinical implications in regard to effectively targeting those cells within a tumor cell population that exhibit stable elevations in intrinsic Δψm and are most likely to contribute to tumor progression.

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Section: Discussionmentioning

confidence: 99%

Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

2011

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“…This high-level ROS generation promotes genetic instability in tumors, favors growth, chemotherapeutic escape, and evasion of senescence, all contributing to the increase in tumor malignancy. Therefore, the mitochondrion, where ROS is mainly produced, seems to play an important role in the tumorigenic phenotype 76. The mitochondrial DNA (mtDNA) encodes 13 of the electron transport chain proteins, and consequently, alterations in these coding genes lead to OXPHOS malfunction and inability to synthesize ATP and to reduce oxygen, which generates ROS.…”

Section: Metabolic Modifications In Cancer Cells and Potential Targetmentioning

confidence: 99%

Metabolism and Brain Cancer

Marie

Shinjo

2011

Clinics

114

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Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.

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“…The “Warburg Effect” refers to the tumor's use of aerobic glycolysis to provide energy as well as biomolecules for growth regardless of the availability of oxygen. Dysregulation of genes involved in glycolysis and glycolytic transport to the mitochondria of tumor cells has been reported, as have alterations to the mitochondria themselves [6]. Metabolic dysregulation can also be a result of loss of p53 and subsequent upregulation of serine-threonine protein kinase (Akt) which can lead to the production of an overabundance of ATP [7].…”

Section: Introductionmentioning

confidence: 99%

The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma

et al. 2012

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IntroductionThe ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas.MethodsWe used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging.ResultsAnimals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days.ConclusionsKC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

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The importance of mitochondria in the tumourigenic phenotype: Gliomas as the paradigm (Review)

Cited by 13 publications

References 108 publications

Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

Intrinsic Mitochondrial Membrane Potential and Associated Tumor Phenotype Are Independent of MUC1 Over-Expression

Metabolism and Brain Cancer

The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma

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