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Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells.
Journal of Lipid Research ( IF 6.5 ) Pub Date : 2019-07-30 , DOI: 10.1194/jlr.ra119000251
Li-Pin Kao 1 , Samy A F Morad 2 , Traci S Davis 1 , Matthew R MacDougall 1 , Miki Kassai 1 , Noha Abdelmageed 3 , Todd E Fox 4 , Mark Kester 5 , Thomas P Loughran 6 , Jose' L Abad 7 , Gemma Fabrias 7 , Su-Fern Tan 8 , David J Feith 6 , David F Claxton 9 , Sarah Spiegel 10 , Kelsey H Fisher-Wellman 11 , Myles C Cabot 1
Affiliation  

The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.

中文翻译:

化疗选择压力改变耐药 HL-60 细胞中的鞘脂组成和线粒体生物能。

柔红霉素 (dnr) 和阿糖胞苷 (Ara-C) 的组合是治疗急性髓性白血病 (AML) 的基石;对这些药物的耐药性是治疗失败的主要原因。神经酰胺是一种鞘脂 (SL),在化疗引起的癌细胞凋亡中发挥着关键作用。在这里,我们研究了 Ara-C 和 dnr 化疗选择压力对 AML 细胞系 HL-60 中 SL 组成和酶活性的影响。选择在含有 Ara-C 和 dnr 的培养基(分别为 HL-60/Ara-C 和 HL-60/dnr)中生长的抗性细胞,显示葡萄糖神经酰胺合酶、酸性神经酰胺酶 (AC)、和鞘氨醇激酶 1 (SPHK1);与亲代细胞相比,对神经酰胺的抵抗力更强;并对 SL 代谢抑制剂表现出敏感性。脂质组学分析显示,与亲代细胞和 HL-60/Ara-C 细胞相比,HL-60/dnr 细胞中普遍存在神经酰胺缺陷,并且 1-磷酸鞘氨醇 (S1P) 和 1-磷酸神经酰胺 (C1P) 水平显着上升。两种化疗选择的细胞还表现出线粒体生物合成的全面上调,这与对氧化磷酸化的高度依赖一致,氧化磷酸化的这种特性通过暴露于 AC 和 SPHK1 抑制剂而被部分逆转,并且支持磷酸化系统在耐药中的作用。总之,dnr 和 Ara-C 选择压力会导致神经酰胺水平急剧降低,S1P 和 C1P 大幅增加,同时线粒体重塑增强,从而增强细胞弹性。因此,
更新日期:2020-08-21
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