title: Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition.
abstract: The high glucose consumption of tumor cells even in an oxygen-rich environment, referred to as the Warburg effect, has been noted as a nearly universal biochemical characteristic of cancer cells. Targeting the glycolysis pathway has been explored as an anti-cancer therapeutic strategy to eradicate cancer based on this fundamental biochemical property of cancer cells. Oncoproteins such as Akt and c-Myc regulate cell metabolism. Accumulating studies have uncovered various molecular mechanisms by which oncoproteins affect cellular metabolism, raising a concern as to whether targeting glycolysis will be equally effective in treating cancers arising from different oncogenic activities. Here, we established a dual-regulatable FL5.12 pre-B cell line in which myristoylated Akt is expressed under the control of doxycycline, and c-Myc, fused to the hormone-binding domain of the human estrogen receptor, is activated by 4-hydroxytamoxifen. Using this system, we directly compared the effect of these oncoproteins on cell metabolism in an isogenic background. Activation of either Akt or c-Myc leads to the Warburg effect as indicated by increased cellular glucose uptake, glycolysis, and lactate generation. When cells are treated with glycolysis inhibitors, Akt sensitizes cells to apoptosis, whereas c-Myc does not. In contrast, c-Myc but not Akt sensitizes cells to the inhibition of mitochondrial function. This is correlated with enhanced mitochondrial activities in c-Myc cells. Hence, although both Akt and c-Myc promote aerobic glycolysis, they differentially affect mitochondrial functions and render cells susceptible to the perturbation of cellular metabolic programs.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Fan
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D002460:Cell Line; D019069:Cell Respiration / Q000502:physiology; D004318:Doxycycline / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D005227:Fatty Acids; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; C016601:afimoxifene; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D004318:Doxycycline