Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells.

Autor: Bhanot H; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Reddy MM; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Nonami A; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Weisberg EL; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Bonal D; Center for Biomedical Imaging in Oncology (CBIO), Lurie Family Imaging Center (LFIC), Boston, MA, 02215, USA., Kirschmeier PT; Center for Biomedical Imaging in Oncology (CBIO), Lurie Family Imaging Center (LFIC), Boston, MA, 02215, USA., Salgia S; Department of Medical Oncology, Boston, MA, 02215, USA., Podar K; National Center for Tumor Diseases (NCT), Heidelberg, Germany.; University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany., Galinsky I; Department of Medical Oncology, Boston, MA, 02215, USA., Chowdary TK; School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, India., Neuberg D; Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Tonon G; San Raffaele Scientific Institute, Milan, Italy., Stone RM; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Asara J; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.; Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA02215, USA., Griffin JD; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Sattler M; Department of Medical Oncology, Boston, MA, 02215, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2015 Jul; Vol. 29 (7), pp. 1555-1563. Date of Electronic Publication: 2015 Feb 23.
DOI: 10.1038/leu.2015.46
Abstrakt: 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.
Databáze: MEDLINE