Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.
Alterations in sphingolipid composition and mitochondrial bioenergetics represent synergistic therapeutic vulnerabilities linked to multidrug resistance in leukemia.
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鞘脂组成和线粒体生物能的改变代表与白血病中多药耐药性相关的协同治疗脆弱性。
DOI：
10.1096/fj.202101194rrr
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发表时间：
2022-01
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鞘脂（SL）代谢和线粒体生物能量学的改变是涉及癌细胞对化疗反应（包括化疗耐药）的关键因素。在本研究中，我们利用急性髓性白血病（AML）细胞系，选择对各种化疗药物难以耐受的细胞系，探索SL代谢与支持多药耐药（MDR）的线粒体生物学之间的相互作用。与先前在阿糖胞苷或柔红霉素耐药的AML细胞中发现的结果一致，相对于对化疗敏感的野生型对照，HL-60细胞对长春新碱（HL60/VCR）难耐，呈现出SL酶表达和脂质组组成的改变。这种变化的典型表现为各种神经酰胺解毒酶的表达上调，以及神经酰胺、葡萄糖神经酰胺和鞘磷脂（SM）分子种类的相应变化。就线粒体而言，尽管基础呼吸和最大呼吸量均持续增加，但对氧化磷酸化（OXPHOS）系统的直接询问揭示了HL60/VCR以及多个MDR模型系统的内在缺陷。基于增加SL和线粒体通量以支持MDR表型的明显需求，我们探索了针对每种途径设计的组合治疗范式。值得注意的是，尽管外周血单核细胞（PBMC）的细胞毒性很小，但在多种MDR白血病模型中，共同靶向SL代谢和呼吸复合体I （CI）诱导的协同细胞毒性一致。总之，这些数据强调了细胞鞘脂和线粒体代谢之间的密切联系，并表明通过这两种途径的药物干预可能代表了一种新的治疗耐多药的策略。
Modifications in sphingolipid (SL) metabolism and mitochondrial bioenergetics are key factors implicated in cancer cell response to chemotherapy, including chemotherapy resistance. In the present work, we utilized acute myeloid leukemia (AML) cell lines, selected to be refractory to various chemotherapeutics, to explore the interplay between SL metabolism and mitochondrial biology supportive of multidrug resistance (MDR). In agreement with previous findings in cytarabine or daunorubicin resistant AML cells, relative to chemosensitive wildtype controls, HL-60 cells refractory to vincristine (HL60/VCR) presented with alterations in SL enzyme expression and lipidome composition. Such changes were typified by upregulated expression of various ceramide detoxifying enzymes, as well as corresponding shifts in ceramide, glucosylceramide, and sphingomyelin (SM) molecular species. With respect to mitochondria, despite consistent increases in both basal respiration and maximal respiratory capacity, direct interrogation of the oxidative phosphorylation (OXPHOS) system revealed intrinsic deficiencies in HL60/VCR, as well as across multiple MDR model systems. Based on the apparent requirement for augmented SL and mitochondrial flux to support the MDR phenotype, we explored a combinatorial therapeutic paradigm designed to target each pathway. Remarkably, despite minimal cytotoxicity in peripheral blood mononuclear cells (PBMC), co-targeting SL metabolism, and respiratory complex I (CI) induced synergistic cytotoxicity consistently across multiple MDR leukemia models. Together, these data underscore the intimate connection between cellular sphingolipids and mitochondrial metabolism and suggest that pharmacological intervention across both pathways may represent a novel treatment strategy against MDR.