The carnitine system and cancer metabolic plasticity

Cell Death & Disease, Feb 2018

Metabolic flexibility describes the ability of cells to respond or adapt its metabolism to support and enable rapid proliferation, continuous growth, and survival in hostile conditions. This dynamic character of the cellular metabolic network appears enhanced in cancer cells, in order to increase the adaptive phenotype and to maintain both viability and uncontrolled proliferation. Cancer cells can reprogram their metabolism to satisfy the energy as well as the biosynthetic intermediate request and to preserve their integrity from the harsh and hypoxic environment. Although several studies now recognize these reprogrammed activities as hallmarks of cancer, it remains unclear which are the pathways involved in regulating metabolic plasticity. Recent findings have suggested that carnitine system (CS) could be considered as a gridlock to finely trigger the metabolic flexibility of cancer cells. Indeed, the components of this system are involved in the bi-directional transport of acyl moieties from cytosol to mitochondria and vice versa, thus playing a fundamental role in tuning the switch between the glucose and fatty acid metabolism. Therefore, the CS regulation, at both enzymatic and epigenetic levels, plays a pivotal role in tumors, suggesting new druggable pathways for prevention and treatment of human cancer.

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The carnitine system and cancer metabolic plasticity

Abstract Metabolic flexibility describes the ability of cells to respond or adapt its metabolism to support and enable rapid proliferation, continuous growth, and survival in hostile conditions. This dynamic character of the cellular metabolic network appears enhanced in cancer cells, in order to increase the adaptive phenotype and to maintain both viability and uncontrolled proliferation. Cancer cells can reprogram their metabolism to satisfy the energy as well as the biosynthetic intermediate request and to preserve their integrity from the harsh and hypoxic environment. Although several studies now recognize these reprogrammed activities as hallmarks of cancer, it remains unclear which are the pathways involved in regulating metabolic plasticity. Recent findings have suggested that carnitine system (CS) could be considered as a gridlock to finely trigger the metabolic flexibility of cancer cells. Indeed, the components of this system are involved in the bi-directional transport of acyl moieties from cytosol to mitochondria and vice versa, thus playing a fundamental role in tuning the switch between the glucose and fatty acid metabolism. Therefore, the CS regulation, at both enzymatic and epigenetic levels, plays a pivotal role in tumors, suggesting new druggable pathways for prevention and treatment of human cancer. Facts Malignant cells are capable of creating an equilibrium between producing and consuming energy and metabolic intermediates synthesis to sustain growth and survival. Metabolic plasticity makes cancer cells more aggressive and able to metastasize. Oncogenic pathways, nutrient availability, and microenvironment influence cell metabolism. The carnitine system is a pivotal mediator in cancer metabolic plasticity, intertwining key pathways, factors, and metabolites that supply an energetic and biosynthetic demand for cancer cells. MiRnas and metabolic enzymes regulate metabolic plasticity through the carnitine system suggesting their use for developing new therapeutic strategies. Open questions What is the role of the carnitine system in cancer metabolism rewiring? Is the carnitine system dysregulated in cancerogenesis? What is the purpose of epigenetics in the modulation of the expression of proteins belonging to the carnitine system? Is it possible to explore new anticancer treatment targeting component(s) of the carnitine system? Cancer cells must maintain metabolic homeostasis in a wide range of conditions, including harsh microenvironments in which cancer cells must continue to meet the high bio-energetic demand in order to undergo replication1. These cells achieve metabolic homeostasis by regulating the dynamics of nutrients present in the microenvironment, and the ability of cancer cells to utilize them to produce energy and to synthesize macromolecules. It is feasible that the capability of cancer cells to employ alternative nutrients in different environments is critical in supporting and affecting their survival. However, tumor cell metabolic plasticity is not just as the result of the metabolic dynamic impact changes induced by the microenvironment and fuel choices of cancer cells. Instead, it is more appropriate to envision metabolic plasticity regarding uptake of alternative metabolic substrates and promotion of metabolic rewiring as a built-in feature that has evolved to allow cancer cells to constantly adapt to changing intracellular- and extracellular metabolic conditions2. Intracellular metabolite concentrations have to fine-tune the signaling networks governing metabolic pathways independently of the environment to ensure a balance between the availability of nutrients and the cellular capacity to use them effectively. Metabolites, through post-translational modifications of metabolite-sensitive protein (i.e. acetylation, methylation or glycosylation), transduce the information on the cell metabolic status, and modulate the activities of signaling proteins, enzymes, and transcriptional regulators3. Therefore, it is necessary to understand how a variety of intrinsic and extrinsic factors are integrated to create the metabolic flexibility and to reduce the metabolic dependencies dictated by oncogenic signaling. In this review, we identify the carnitine system (CS) as a gridlock to finely trigger the cancer cells’ metabolic plasticity. In this context, the CS regulation at both the enzyme and the gene level plays a pivotal role in the metabolic flux modulation of tumors, and scientists can target them for therapeutic purposes. Nutrients and energy acquisition strategies in cancer cells metabolism Cancer cells prioritize aerobic glycolysis (Warburg effect), as the primary fuel and convert excess pyruvate to lactate independently from oxygen availability4. In addition, glucose is considered to be the primary carbon source that contributes to the production of mitochondrial citrate in cancer cells. The citrate in excess of mitoch (...truncated)


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Mariarosa Anna Beatrice Melone, Anna Valentino, Sabrina Margarucci, Umberto Galderisi, Antonio Giordano, Gianfranco Peluso. The carnitine system and cancer metabolic plasticity, Cell Death & Disease, 2018, Issue: 9, DOI: 10.1038/s41419-018-0313-7