Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation
Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation
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DOI：
10.1016/j.canlet.2016.04.040
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发表时间：
2016-07-28
期刊：
影响因子：
9.7
通讯作者：
Hu, Yumin
中科院分区：
文献类型：
--
作者：
Huang, Amin;Ju, Huai-Qiang;Hu, Yumin
FMS样酪氨酸激酶-3（FLT 3）受体跨膜区的内部串联重复（ITD）是成人急性髓性白血病（AML）中常见的突变类型，由于出现耐药性，患者对FLT 3抑制剂的反应似乎是短暂的。我们建立了两种携带FLT 3/ITD突变的索拉非尼耐药细胞系，包括鼠BaF 3/ITD-R和人MV 4 -11-R细胞系。抗性细胞和亲本细胞的基因表达谱分析表明，差异表达基因的最高排名的分子和细胞功能与线粒体功能障碍有关。鼠和人耐药细胞系均显示较长的倍增时间，沿着线粒体呼吸链活性的显著抑制和糖酵解的显著上调。索拉非尼抗性细胞表现出大多数糖酵解酶的表达增加，包括己糖激酶2，其也在线粒体部分中高度表达，并且与对凋亡性细胞死亡的抗性相关。索拉非尼耐药细胞对包括2-脱氧葡萄糖和3-溴丙酮酸丙酯在内的许多糖酵解抑制剂是间接敏感的。我们的研究揭示了索拉非尼耐药细胞的代谢特征，并表明糖酵解抑制可能会覆盖这种耐药，并保证进一步的临床研究。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Internal tandem duplication (ITD) of the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3) receptor is a common type of mutation in adult acute myeloid leukemia (AML), and patient response to FLT3 inhibitors appears to be transient due to the emergence of drug resistance. We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, including the murine BaF3/ITD-R and human MV4-11-R cell lines. Gene expression profile analysis of the resistant and parental cells suggests that the highest ranked molecular and cellular functions of the differentially expressed genes are related to mitochondrial dysfunction. Both murine and human resistant cell lines display a longer doubling time, along with a significant inhibition of mitochondrial respiratory chain activity and substantial upregulation of glycolysis. The sorafenib-resistant cells exhibit increased expression of a majority of glycolytic enzymes, including hexokinase 2, which is also highly expressed in the mitochondrial fraction and is associated with resistance to apoptotic cell death. The sorafenib-resistant cells are collaterally sensitive to a number of glycolytic inhibitors including 2-deoxyglucose and 3-bromopyruvate propylester. Our study reveals a metabolic signature of sorafenib-resistant cells and suggests that glycolytic inhibition may override such resistance and warrant further clinical investigation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.