1. Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells.
- Author
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Bhanot, H, Reddy, M M, Nonami, A, Weisberg, E L, Bonal, D, Kirschmeier, P T, Salgia, S, Podar, K, Galinsky, I, Chowdary, T K, Neuberg, D, Tonon, G, Stone, R M, Asara, J, Griffin, J D, and Sattler, M
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MYELOID leukemia , *GLUCOSE metabolism , *GLYCOGEN synthases , *LEUKEMIA , *GENOMICS , *ANIMALS , *APOPTOSIS , *BIOCHEMISTRY , *CELL physiology , *EPITHELIAL cells , *FLOW cytometry , *GLYCOGEN , *GLYCOLYSIS , *MICE , *PHOSPHORYLATION , *PHOSPHOTRANSFERASES , *POLYMERASE chain reaction , *PROGNOSIS , *RNA , *SURVIVAL , *TRANSFERASES , *CASE-control method , *REVERSE transcriptase polymerase chain reaction , *CANCER cell culture - Abstract
The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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