Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells

Since many oncogenes, including BCR-ABL, may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial complex subunits thus causing alterations of glucose metabolism. BCR-ABL-driven K562 and KCL-22 cells were incubated with increasing concentrations of imatinib to preliminarily test drug sensitivity. Then untreated and treated cells were analyzed for levels of BCR-ABL signaling mediators and key proteins of glycolytic cascade and oxidative phosphorylation. Effective inhibition of BCR-ABL caused a concomitant reduction of p-ERK1/2, p-AKT, phosphorylated form of STAT3 (at Tyr705 and Ser727), c-Myc and cyclin D1 along with an increase of cleaved PARP and caspase 3 at 48 h after treatment. Furthermore, a strong reduction of the hexokinase II (HKII), phosphorylated form of PKM2 (at Tyr105 and Ser37) and lactate dehydrogenase A (LDH-A) was observed in response to imatinib along with a strong upregulation of mitochondrial complexes (OXPHOS). According to these findings, a significant reduction of glucose consumption and lactate secretion along with an increase of intracellular ATP levels was observed in response to imatinib. Our findings indicate that imatinib treatment of BCR-ABL-driven human leukemia cells reactivates mitochondrial oxidative phosphorylation thus allowing potential co-targeting of BCR-ABL and OXPHOS.

Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells

Query:  [X]
Options:	AnyAllExact    Extended      IBB affiliation
	ORAND
Authors:  [X]
Paper type:  [X]
Start date:  [X]
End date:  [X]
Site:	All sitesNaples - De AmicisNaples - CastellinoTurin
	StaffResearch areasActivitiesBibliographyPapersCMSGeneric [Clear form]