Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress

Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc and...

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Bibliographic Details
Published in:Molecular oncology 2015-03, Vol.9 (3), p.601-616
Main Authors: Maya-Mendoza, Apolinar, Ostrakova, Jitka, Kosar, Martin, Hall, Arnaldur, Duskova, Pavlina, Mistrik, Martin, Merchut-Maya, Joanna Maria, Hodny, Zdenek, Bartkova, Jirina, Christensen, Claus, Bartek, Jiri
Format: Article
Language:English
Subjects:
Addictions
Cancer
Cell cycle
Cell Death
Cell growth
Cell Line, Tumor
Cell Proliferation
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA Damage
DNA damage response
DNA fork progression
DNA Replication - genetics
Energy metabolism
Energy Metabolism - genetics
Fibroblasts
Genes, ras
Glycolysis
Homeostasis
Humans
Kinases
Metabolism
Mitochondria
Mitochondria - metabolism
Mutation
Myc
Myc protein
Oncogenes
Oxidative stress
Oxidative Stress - genetics
Oxygen consumption
Phosphorylation
Proteins
Proto-Oncogene Proteins c-myc - genetics
Ras
Reactive oxygen species
Replication
Replication stress
Sarcoma
Senescence
Stress, Physiological - genetics
Superoxide
Tumorigenesis
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Summary:Both Myc and Ras oncogenes impact cellular metabolism, deregulate redox homeostasis and trigger DNA replication stress (RS) that compromises genomic integrity. However, how are such oncogene-induced effects evoked and temporally related, to what extent are these kinetic parameters shared by Myc and Ras, and how are these cellular changes linked with oncogene-induced cellular senescence in different cell context(s) remain poorly understood. Here, we addressed the above-mentioned open questions by multifaceted comparative analyses of human cellular models with inducible expression of c-Myc and H-RasV12 (Ras), two commonly deregulated oncoproteins operating in a functionally connected signaling network. Our study of DNA replication parameters using the DNA fiber approach and time-course assessment of perturbations in glycolytic flux, oxygen consumption and production of reactive oxygen species (ROS) revealed the following results. First, overabundance of nuclear Myc triggered RS promptly, already after one day of Myc induction, causing slow replication fork progression and fork asymmetry, even before any metabolic changes occurred. In contrast, Ras overexpression initially induced a burst of cell proliferation and increased the speed of replication fork progression. However, after several days of induction Ras caused bioenergetic metabolic changes that correlated with slower DNA replication fork progression and the ensuing cell cycle arrest, gradually leading to senescence. Second, the observed oncogene-induced RS and metabolic alterations were cell-type/context dependent, as shown by comparative analyses of normal human BJ fibroblasts versus U2-OS sarcoma cells. Third, the energy metabolic reprogramming triggered by Ras was more robust compared to impact of Myc. Fourth, the detected oncogene-induced oxidative stress was due to ROS (superoxide) of non-mitochondrial origin and mitochondrial OXPHOS was reduced (Crabtree effect). Overall, our study provides novel insights into oncogene-evoked metabolic reprogramming, replication and oxidative stress, with implications for mechanisms of tumorigenesis and potential targeting of oncogene addiction. •Ras and Myc oncogenes induce replication stress, yet with distinct kinetics.•Myc-induced replication stress precedes alterations in energy metabolism.•Oncogene-induced oxidative stress reflects non-mitochondrial ROS.•Oncogene-evoked metabolic alterations are cell-type/context-dependent.•Ras reprograms bioenergetic metab
ISSN:1574-7891
1878-0261
DOI:10.1016/j.molonc.2014.11.001