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Signaling Pathways That Overactivate Metabolism and Drive Neoplasia, in Rhabdomyosarcoma

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Signaling Pathways That Overactivate Metabolism and Drive Neoplasia, in Rhabdomyosarcoma Journal of Research and Practice on the Musculoskeletal System JOURNAL OF RESEARCH AND PRACTICE ON THE MUSCULOSKELETAL SYSTEM Review Article Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma Christos P. Tselios1,2, George I. Lambrou1,2,3 1Laboratory for Research of the Musculoskeletal System “Th. Garofalidis”, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens KAT, Greece; 2Postgraduate Program “Metabolic Bones Diseases”, National and Kapodistrian University of Athens, Medical School, Athens, Greece; 3First Department of Pediatrics, National and Kapodistrian University of Athens, Choremeio Research Laboratory, Goudi, Athens, Greece Abstract The functional status of a cell is expressed in its metabolic activity. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Thus, cancer- associated metabolic alterations, i.e. metabolic over-activation through signaling pathways alterations, have emerged as a cancer hallmark. Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children, adolescents and adults. Signaling pathway alterations present in this cancer can be related to increased metabolic activity and drive neoplasia. In this review first of all, we would like to enlighten cancer and particular RMS metabolism. Further, we aim to summarize several pathways related to oncogenic drivers affecting metabolism of RMS cells in order to simulate them (in other studies) with a system biology approach. The understanding of the common mechanisms that transform physiological cells to malignant may reveal novel therapeutic targets and strategies that may improve the currently poor outcome for patients with RMS. Keywords: Signaling, Pathway, Metabolism, Neoplasia, Rhabdomyosarcoma Introduction adhesion molecules, proteases, anti-apoptotic factors, DNA repair factors, cell cycle and cell metabolism factors. NF-kB, In several research studies, evidence emerged that at STAT3 and AP-1 thereby control cell transformation, cell the molecular level most chronic diseases, including cancer, survival, proliferation, invasion, angiogenesis, metastasis, are caused by a deregulated inflammatory response. chemoresistance, and radioresistance of cancer. Deregulated Characterization of protein families of transcription factors activation of NF-kB, STAT3 and AP-1 family proteins is NF-κB, AP-1 and STAT3 which have gene targets that often associated with transition of cells from a differentiated include inflammatory mediators and adhesion molecules phenotype to a stem cell-like unit, which may abnormally provided the molecular basis for the role of inflammation retain features of the differentiated cell. Common theme is the in cancer: many of those inflammatory mediators influence presence of features that are essential for the preservation of transendothelial migration of inflammatory cells and vascular cell functions under unfavorable conditions related to stress, permeability. Additionally, molecules normally expressed in circulating cells of the immune system are often abnormally expressed in metastatic cells of solid tumors, thereby providing a mechanistic explanation for cancer progression. The authors have no conflict of interest. Fewer genetic or epigenetic changes are required for the Corresponding author: George I. Lambrou, First Department development of liquid tumors than for solid tumors: this is one of Paediatrics, National and Kapodistrian University of Athens, reason that epidemiologically liquid tumors reportedly need Choremeio Research Laboratory, Hematology and Oncology a shorter period of exposure to potent carcinogenic agents. Unit, Thivon & Levadeias 8, 11527, Goudi, Athens, Greece Inflammatory pathways that affect NF-kB, STAT3 and E-mail: [email protected] AP-1 are activated by tobacco, stress, dietary agents, obesity, Edited by: Konstantinos Stathopoulos alcohol, infectious agents, irradiation, and environmental Accepted 7 January 2019 Published under Creative Common License CC BY-NC-SA 4.0 (Attribution-Non Commercial-ShareAlike) Common License CC BY-NC-SA 4.0 (Attribution-Non Creative Published under stimuli, and in turn regulate expression of cytokines, www.jrpms.eu 10.22540/JRPMS-03-017 JRPMS | March 2019 | Vol. 3, No. 1 | 17-25 17 C.P. Tselios, G.I. Lambrou both external and internal. Inflammatory mediators and radicals-which can initiate damage to macromolecules and neighboring cells affect stem cell function drastically. to intracellular and extracellular signaling pathways-and At the same time besides inflammation, energy the overexpression of a mitochondrial uncoupling protein consumption and metabolism in cancer is considered to be of has been shown to play important role in malignant onset, paramount importance towards the understanding of tumor progression and immortality8,11. mechanics. To our knowledge, there is not enough information Studies using MCF10 cells (a normal human mammary available on the metabolic mechanisms underlying tumor epithelial cell line) suggested that the glucose flux through cells. It might be bold to say, but not exaggerated, that a the Pentose Phosphate Pathway (PPP), in parallel to possible answer in the treatment of cancer, lies within the glycolysis, is also increased in cancer cells12. Increased PPP delicate mechanisms of metabolic processes. The governing rate allows producing enough ribose for nucleotide synthesis idea was that the Warburg effect is rather the consequence and NADPH for lipid biosynthesis and maintenance of cell’s of the cancer process, mainly due to hypoxic growth, and not redox status. Although glycolysis predominates as the main to a prerequisite for cancer progression and proliferation ATP supply, anti-glycolytic treatment in mature MCTs (multi- per se1. However, it has recently been reported that the cellular tumor spheroids) has shown only a marginal effect on process of aerobic glycolysis is reversible from very simple inhibiting tumor proliferation, suggesting that cells inside the compounds such Dichloroacetate (DCA)2,3. In actual fact, spheroids remain significantly dependent on the alternative the aspect of interfering with cancer metabolic pathways ATP derived from mitochondria13. as a mean for tumor treatment and therapy seems to be of To explain both the way ATP is produced via a low utmost importance4. This became apparent from discoveries efficiency method, i.e. glycolysis, despite extremely high made in the field of metabolomics involving molecules energy demand of the tumor cells, and reasonably explain previously thought to be solely metabolic and without the the “autophagy paradox”14, a new model is hypothesized: slightest suspicion for regulatory functions. Such molecules the reverse Warburg effect. According to this hypothesis, include diacylglycerol5, ceramides and sphingosine, which glycolysis occurs in mesenchymal stroma cells under the are essential in cell proliferation and apoptosis6 as well as activation of neighboring cancer cells. Furthermore, an pyridine nucleotides, which play an essential role in signal increased formation of recycled nutrients is produced. This transduction7. high-energy metabolism is transferred to the neighboring Nowadays, it is clear, that metabolites or metabolic cancer cells by the orientation of transport in the tricarboxylic molecules, not only participate in metabolic processes acid (TCA) cycle. The consequence is that the OXPHOS which are dealing with the energy production and the increases enhancing ATP production, thus constituting thermodynamical conservation of the cell, but also metabolic coupling8. possess multiple functions especially on the level of signal Going back to the Warburg effect, its establishment in transduction. Consequently, similar molecules used, such cancer cells is the result of altered signaling pathways due as nutrients, could afford target therapy. Thus, in the to mutations that lead to the activation of growth promoting present work we attempted to review some of the metabolic oncogenes and inactivation of tumor suppressors. mechanisms of tumor cells focusing on the example of Particularly, signaling alterations are found in: PI3K/AKT/ rhabdomyosarcoma. mTOR pathway, RAS/RAF/MEK)/ERK kinase cascade, HIF- 1 transcription factor, MYC transcription factor, AMPK Cancer metabolism signaling, P53 transcription factor15. Cancer cells need greater amount of energy because In cancer, the PI3K/AKT/mTOR pathway reprograms they grow rapidly. Otto Warburg found that cancer cells glucose metabolism to fuel cell growth15. Aberrant activation prefer to produce ATP by glycolysis rather than by oxidative of this pathway drives tumor progression independence phosphorylation (OXPHOS) even in the presence of ample on extrinsic growth factor stimulation through mutations oxygen8. This finding was later termed the Warburg effect in tumor suppression genes, such as PTEN, mutations in also known as “aerobic glycolysis”. It is suggested that tumor the components of the PI3K complex itself or by hyper- cells preferentially used aerobic glycolysis over OXPHOS for activation of RTKs16. Activated AKT stimulates glycolysis by glucose-dependent ATP production due to mitochondrial phosphorylating key glycolytic enzymes, such as hexokinase impairments9. Main characteristics of Warburg effect are 2 (HK2) and phosphofructokinase 2 (PFK2) which is an an increased glucose uptake and synthesis
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