Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells
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DOI：
10.3390/ijms20133134
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Iommelli, Francesca
中科院分区：
文献类型：
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作者：
De Rosa, Viviana;Monti, Marcello;Iommelli, Francesca
由于许多致癌基因，包括BCR-ABL，可能促进糖酵解表型的获得和维持，我们测试了用伊马替尼（一种选择性BCR-ABL抑制剂）治疗BCR-ABL驱动的人白血病细胞是否可以调节关键糖酵解酶和线粒体复合物亚基的表达，从而引起糖代谢的改变。bcr - abl驱动的K562和KCL-22细胞在增加伊马替尼浓度的条件下孵育，初步检测药物敏感性。然后分析未处理和处理细胞的BCR-ABL信号介质和糖酵解级联和氧化磷酸化关键蛋白的水平。BCR-ABL的有效抑制在治疗后48小时引起p-ERK1/2、p-AKT、STAT3磷酸化形式（Tyr705和Ser727）、c-Myc和cyclin D1的减少，以及裂解PARP和caspase 3的增加。此外，观察到伊马替尼对己糖激酶II （HKII）、PKM2 （Tyr105和Ser37）磷酸化形式和乳酸脱氢酶a （LDH-A）的强烈降低，以及线粒体复合物（OXPHOS）的强烈上调。根据这些发现，观察到伊马替尼对葡萄糖消耗和乳酸分泌的显著减少以及细胞内ATP水平的增加。我们的研究结果表明，伊马替尼治疗BCR-ABL驱动的人白血病细胞可重新激活线粒体氧化磷酸化，从而可能共同靶向BCR-ABL和OXPHOS。
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.