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Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States

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Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA
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Systems, Synthetic and Physical Biology Program, Rice University, Houston, TX 77005, USA
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Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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Department of Bioengineering, Rice University, Houston, TX 77005, USA
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Department of Biosciences, Rice University, Houston, TX 77005, USA
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Physics and Astronomy, Rice University, Houston, TX 77005, USA
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Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Cells 2018, 7(3), 21; https://doi.org/10.3390/cells7030021
Received: 7 February 2018 / Revised: 1 March 2018 / Accepted: 8 March 2018 / Published: 13 March 2018
Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective. View Full-Text
Keywords: cancer metabolism; Warburg effect; oxidative phosphorylation; OXPHOS; mitochondrial respiration; hybrid metabolic phenotype; metabolic plasticity; tumorigenesis; metastasis; EMT; stemness cancer metabolism; Warburg effect; oxidative phosphorylation; OXPHOS; mitochondrial respiration; hybrid metabolic phenotype; metabolic plasticity; tumorigenesis; metastasis; EMT; stemness
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Jia, D.; Park, J.H.; Jung, K.H.; Levine, H.; Kaipparettu, B.A. Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells 2018, 7, 21.

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