ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells.
ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells.
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ERK/Drp1 依赖性线粒体分裂参与 MSC 诱导的 T 细胞急性淋巴细胞白血病细胞的耐药性。
DOI：
10.1038/cddis.2016.370
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发表时间：
2016-11-10
影响因子：
9
通讯作者：
Xiang AP
中科院分区：
文献类型：
--
作者：
Cai J;Wang J;Huang Y;Wu H;Xia T;Xiao J;Chen X;Li H;Qiu Y;Wang Y;Wang T;Xia H;Zhang Q;Xiang AP
骨髓微环境促进白血病细胞的增殖和存活，有助于疾病复发。骨髓间充质干细胞（MSCs）通过可溶性因子和细胞粘附促进肿瘤化疗耐药性。然而，很少有人知道骨髓间充质干细胞对T细胞急性淋巴细胞白血病（T-ALL）细胞的线粒体动力学的影响，或者这可能会影响这些细胞的耐药性。在这里，我们测试了间接（Transwell）和直接共培养策略，发现MSC保护T-ALL细胞在两种培养条件下免受化疗细胞死亡和细胞毒性。此外，与Transwell系统相比，直接接触系统中的细胞活力更高。我们进一步表明，T-ALL细胞暴露于MSC降低了线粒体活性氧（ROS）水平，并促进了糖酵解前的转变，其特征是葡萄糖摄取和乳酸产生增加，同时三磷酸腺苷产生和线粒体膜电位降低。在与MSC共培养的T-ALL细胞中，由于细胞外信号调节激酶激活介导的促分裂因子，动力蛋白相关蛋白1（Drp 1），在残基S616处的磷酸化，T-ALL细胞的线粒体形态从伸长变为碎片。与此一致，S616-磷酸化Drp 1的表达重现了与MSC共培养的T-ALL细胞中观察到的线粒体动力学、线粒体ROS水平、代谢转换和化疗耐药性。这些发现表明，MSC触发Drp 1激活诱导的线粒体动力学变化的能力对于其保护细胞免受化疗药物的能力至关重要。
The bone marrow microenvironment facilitates the proliferation and survival of leukemia cells, contributing to disease relapse. Bone marrow-derived mesenchymal stem cells (MSCs) are well known to promote cancer chemoresistance via soluble factors and cell adhesion. However, little is known about the effects of MSCs on the mitochondrial dynamics of T-cell acute lymphoblastic leukemia (T-ALL) cells, or how this may influence the chemoresistance of these cells. Here, we tested both indirect (Transwell) and direct coculture strategies, and found that MSCs protected T-ALL cells from chemotherapeutic cell death and cytotoxicity under both culture conditions. In addition, cell viability was higher in the direct contact system compared with the Transwell system. We further showed that exposure of T-ALL cells to MSCs decreased mitochondrial reactive oxygen species (ROS) levels and promoted a pro-glycolytic shift that was characterized by increased glucose uptake and lactate production with concomitant reductions in adenosine triphosphate production and mitochondrial membrane potential. In T-ALL cells cocultured with MSCs, the mitochondrial morphology of T-ALL cells were altered from elongation to fragmentation because of the extracellular signal-regulated kinase activation-mediated phosphorylation of the pro-fission factor, dynamin-related protein 1 (Drp1), at residue S616. Consistent with this, the expression of S616-phosphorylated Drp1 recapitulated the mitochondrial dynamics, mitochondrial ROS levels, metabolic switching and chemoresistance seen in T-ALL cells cocultured with MSCs. These findings suggest that the ability of MSCs to trigger Drp1 activation-induced changes in mitochondrial dynamics is crucial to their ability to protect cells against chemotherapeutic agents.