Παρασκευή 20 Ιανουαρίου 2017

Survival of acute monocytic leukemia cells is driven by fatty acid oxidation-mediated activation of AMPK in bone marrow adipocytes

Leukemia cells in the bone marrow (BM) must meet the biochemical demands of increased cell proliferation by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the BM may provide an effective therapeutic strategy. In this study, we report the discovery of a metabolic role for BM adipocytes in supporting the growth of leukemic blasts. Preventing nutrient starvation-induced apoptosis of leukemic cells by BM adipocytes, as well as the metabolic and molecular mechanisms involved in this process, were investigated using various analytical techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by BM adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with upregulation of PPARγ, FABP4, CD36, and BCL2 genes. Co-culture of AMoL cells with BM adipocyte increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone heat shock proteins. Inhibition of FAO disrupted in these co-cultures metabolic homeostasis, increased reactive oxygen species production, induced the integrated stress response mediator ATF4, and increased apoptosis in AMoL. Our results suggest that BM adipocytes support AMoL cell survival by regulating their metabolic energy balance. Further, they rationalize disruption of FAO in BM adipocytes as a novel therapeutic strategy for AMoL therapy.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2iVwDMJ
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