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: Yongjun Fan, Kathleen G Dickman, Wei-Xing Zong
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 10 Pg. 7324-33 (Mar 05 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20018866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Enzyme Inhibitors
• Estrogen Antagonists
• Fatty Acids
• Proto-Oncogene Proteins c-myc
• Recombinant Fusion Proteins
• Tamoxifen
• afimoxifene
• Proto-Oncogene Proteins c-akt
• Glucose
• Doxycycline

Topics

• Animals
• Anti-Bacterial Agents (metabolism)
• Cell Line
• Cell Respiration (physiology)
• Doxycycline (metabolism)
• Energy Metabolism (physiology)
• Enzyme Activation
• Enzyme Inhibitors (metabolism)
• Estrogen Antagonists (metabolism)
• Fatty Acids (metabolism)
• Glucose (metabolism)
• Glycolysis (physiology)
• Humans
• Mice
• Mitochondria (metabolism)
• Neoplasms (genetics, metabolism)
• Oxidation-Reduction
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Tamoxifen (analogs & derivatives, metabolism)