Aubin 2019 Thesis
|Aubin M (2019) Glucocorticoids and acute lymphoid leukemia: a proteomic approach. Doctoral Dissertation 99.|
Abstract: Glucocorticoids are used in the therapy of acute lymphoid leukemia (ALL) as well as and other lymphoid malignancies. An initial insufficient response to glucocorticoids has been shown to be an important prognostic marker for a bad outcome.
2-Deoxy-glucose (2-DG) is a glucose analog which is not metabolized and sensitizes ALL-cells to non-toxic doses of glucocorticoids and resistant cells to glucocorticoids. However, the underlying molecular mechanism of glucocorticoid-induced cell death and the synergism with 2-DG remains poorly understood.
Prior work has shown a downregulation of the mitochondrial glutamate/H+-symporter (SLC25A22) and the mitochondrial dicarboxylate carrier (SLC25A10) in response to treatment with the glucocorticoid dexamethasone (DEX). Here I analyze the microsomal fraction of treated leukemic cells with a proteomic approach to further elucidate the mechanism.
I show that treatment with 2-DG alone and in combination with DEX leads to increased expression of NMT-1, which has been implicated in the induction of apoptosis, and a reduction of HADH, an enzyme of beta-oxidation.
I also show that inhibition of glycolysis by 2-DG is associated with downregulation of VDAC1. No synergistic effect with DEX can be shown.
The mechanism of synergy between 2-DG and glucocorticoids remains unclear.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer
Organism: Human Tissue;cell: Lymphocyte Preparation: Intact cells, Permeabilized cells
Coupling state: ROUTINE, OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k