Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

中文翻译：

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糖鞘脂生物合成的抑制作用通过在慢性粒细胞白血病中不同地调节ABC转运蛋白来恢复多药耐药性。

癌症的多药耐药性（MDR）来自对结构和功能不同的化学治疗药物的交叉耐药性。特别地，MDR的特征在于ATP结合盒（ABC）超家族转运蛋白的表达和活性增加。鞘脂是例如ABC蛋白在细胞信号转导，膜生物合成和炎症中的底物，它们的产物可促进癌症进展。葡萄糖基神经酰胺（GlcCer）是由葡萄糖基神经酰胺合酶（一种由UDP-葡萄糖神经酰胺葡糖基转移酶（UGCG）基因编码的关键调节酶）产生的普遍存在的鞘糖脂（GSL）。应激细胞会增加神经酰胺的从头生物合成，在UGCG介导掺入GlcCer中后，神经酰胺会恢复至亚毒性水平。考虑到癌细胞似乎能够动员UGCG并增加了神经酰胺清除的GSL含量，这最终导致了化疗失败，因此我们在这里研究了GSL生物合成的抑制作用如何影响慢性粒细胞白血病的MDR表型。我们发现，MDR与较高的UGCG表达和复杂的GSL谱相关。用神经酰胺类似物d-threo-1-（3,4，-乙二氧基）苯基-2-棕榈酰氨基-3-吡咯烷基-1-丙醇（EtDO-P4）抑制UGCG可大大降低GSL和单唾液四己糖神经节苷脂水平，并与标准化学治疗使细胞对线粒体膜电位损失和凋亡敏感。ABC亚科B成员1（ABCB1）的表达减少，并且ABCC介导的外排活动通过与非糖基化神经酰胺的竞争进行调节。一致地，抑制ABCC介导的运输减少了外源C6-神经酰胺的外流。总体而言，UGCG抑制作用损害了MDR白血病的恶性糖表型，通常可通过不同的机制克服耐药性。这项工作揭示了GSL参与化疗失败的情况，其发现表明靶向GSL调节可以帮助控制MDR白血病。