Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2

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Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2

Show simple item record Everett, Peter Clish, Clary B. Polymenis, Michael Ren, Jian-Guo Seth, Pankaj Sukhatme, Vikas Pandurang 2011-11-17T16:23:14Z 2010
dc.identifier.citation Ren, Jian-Guo, Pankaj Seth, Peter Everett, Clary B. Clish, and Vikas P. Sukhatme. 2010. Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS ONE 5(9): e12520. en_US
dc.identifier.issn 1932-6203 en_US
dc.description.abstract Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and CO2 and uses NAD as a cofactor. Higher expression of this enzyme correlates with the degree of cell de-differentiation. We found that ME2 is expressed in K562 erythroleukemia cells, in which a number of agents have been found to induce differentiation either along the erythroid or the myeloid lineage. We found that knockdown of ME2 led to diminished proliferation of tumor cells and increased apoptosis in vitro. These findings were accompanied by differentiation of K562 cells along the erythroid lineage, as confirmed by staining for glycophorin A and hemoglobin production. ME2 knockdown also totally abolished growth of K562 cells in nude mice. Increased ROS levels, likely reflecting increased mitochondrial production, and a decreased \(NADPH/NADP^+\) ratio were noted but use of a free radical scavenger to decrease inhibition of ROS levels did not reverse the differentiation or apoptotic phenotype, suggesting that ROS production is not causally involved in the resultant phenotype. As might be expected, depletion of ME2 induced an increase in the \(NAD^+/NADH\) ratio and ATP levels fell significantly. Inhibition of the malate-aspartate shuttle was insufficient to induce K562 differentiation. We also examined several intracellular signaling pathways and expression of transcription factors and intermediate filament proteins whose expression is known to be modulated during erythroid differentiation in K562 cells. We found that silencing of ME2 leads to phospho-ERK1/2 inhibition, phospho-AKT activation, increased GATA-1 expression and diminished vimentin expression. Metabolomic analysis, conducted to gain insight into intermediary metabolic pathways that ME2 knockdown might affect, showed that ME2 depletion resulted in high orotate levels, suggesting potential impairment of pyrimidine metabolism. Collectively our data point to ME2 as a potentially novel metabolic target for leukemia therapy. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pone.0012520 en_US
dc.relation.hasversion en_US
dash.license LAA
dc.subject biochemistry en_US
dc.subject drug discovery en_US
dc.subject cell biology en_US
dc.subject cell signaling en_US
dc.subject cellular death and stress responses en_US
dc.subject oncology en_US
dc.subject myeloproliferative disorders, including chronic myeloid leukemia en_US
dc.title Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2 en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US Ren, Jian-Guo 2011-11-17T16:23:14Z
dash.affiliation.other HMS^Medicine- Beth Israel-Deaconess en_US

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