Ma Hongye, Zhou Huimin, Li Peng, Song Xiaobo, Miao Xiaoyan, Li Yanping, Jia Li
College of Laboratory Medicine, Dalian Medical University, Dalian, Liaoning Province, China.
Department of Microbiology, Dalian Medical University, Dalian, Liaoning Province, China.
Biochim Biophys Acta. 2014 Sep;1842(9):1681-92. doi: 10.1016/j.bbadis.2014.06.014. Epub 2014 Jun 19.
Sialyl Lewis X (sLe X, CD15s) is a key antigen produced on tumor cell surfaces during multidrug resistance (MDR) development. The present study investigated the effect of α1, 3 fucosyltransferase VII (FucT VII) and α2, 3 sialyltransferase IV (ST3Gal IV) on sLe X oligosaccharides synthesis as well as their impact on MDR development in acute myeloid leukemia cells (AML). FUT7 and ST3GAL4 were overexpressed in three AML MDR cells and bone marrow mononuclear cells (BMMC) of AML patients with MDR by real-time polymerase chain reaction (PCR). A close association was found between the expression levels of FUT7 and ST3GAL4 and the amount of sLe X oligosaccharides, as well as the phenotypic variation of MDR of HL60 and HL60/ADR cells both in vitro and in vivo. Manipulation of these two genes' expression modulated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, thereby regulating the proportionally mutative expression of P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1), both of which are known to be involved in MDR. Blocking the PI3K/Akt pathway by its specific inhibitor LY294002 or Akt short hairpin RNA (shRNA) resulted in the reduced MDR of HL60/ADR cells. This study indicated that sLe X involved in the development of MDR of AML cells probably through FUT7 and ST3GAL4 regulating the activity of PI3K/Akt signaling pathway and the expression of P-gp and MRP1.
唾液酸化路易斯X（sLe X，CD15s）是肿瘤细胞在多药耐药（MDR）形成过程中在其表面产生的关键抗原。本研究调查了α1,3岩藻糖基转移酶VII（FucT VII）和α2,3唾液酸基转移酶IV（ST3Gal IV）对sLe X寡糖合成的影响以及它们对急性髓系白血病细胞（AML）中MDR形成的影响。通过实时聚合酶链反应（PCR）在三种AML多药耐药细胞和患有MDR的AML患者的骨髓单个核细胞（BMMC）中过表达FUT7和ST3GAL4。发现FUT7和ST3GAL4的表达水平与sLe X寡糖的量以及HL60和HL60/ADR细胞在体外和体内的MDR表型变异之间存在密切关联。操纵这两个基因的表达可调节磷酸肌醇-3激酶（PI3K）/Akt信号通路的活性，从而调节已知参与MDR的P-糖蛋白（P-gp）和多药耐药相关蛋白1（MRP1）的比例性变化表达。用其特异性抑制剂LY294002或Akt短发夹RNA（shRNA）阻断PI3K/Akt通路会导致HL60/ADR细胞的多药耐药性降低。本研究表明，sLe X可能通过FUT7和ST3GAL4调节PI3K/Akt信号通路的活性以及P-gp和MRP1的表达而参与AML细胞MDR的形成。
