CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase
CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase
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DOI：
10.1038/sj.leu.2403490
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发表时间：
2004-11-01
期刊：
影响因子：
11.4
通讯作者：
Graves, LM
中科院分区：
文献类型：
--
作者：
Huang, M;Wang, Y;Graves, LM
环戊烯基胞嘧啶(CPEC)是一种CTP合成酶的碳环胞苷类似物，也是联合化疗的实验药物。CPEC(50 NM)可使细胞内CTP耗竭，并诱导K562细胞发生特异性的S期停滞和红系分化。平衡的核苷转运体(ENT1，2)促进CPEC在K562细胞中的摄取，NBMPR和双嘧达莫均能抑制CPEC介导的CTP耗竭和红系分化。与P38 MAPK抑制剂SB203580或SB220025共同孵育可抑制CPEC诱导的K562细胞周期停滞和分化。SB203580还可阻止来氟米特(Leflunomide，LEF)诱导的K562细胞周期停滞和红系分化，来氟米特(Leflunomide，LEF)是一种从头开始的嘧啶途径的非核苷抑制剂，但不影响来氟米特诱导的嘧啶库的耗竭。最后，利用Smart Pool(TM)siRNA对p38 MAPK进行选择性敲除，可显著降低CPEC诱导的K562细胞分化。这些结果表明，在CTP耗竭的条件下，p38 MAP激酶的内源性活性可能是导致K562细胞周期停滞和红系分化所必需的。
Cyclopentenyl cytosine ( CPEC) is a carbocyclic cytidine analog inhibitor of CTP synthetase and experimental drug for combination chemotherapy. CPEC treatment (50 nM) depleted intracellular CTP and induced a specific S-phase arrest and erythroid differentiation of human erythroleukemia K562 cells. The equilibrative nucleoside transporters (ENT1, 2) facilitated uptake of CPEC into K562 cells as evidenced by both NBMPR and dipyridamole inhibition of CPEC-mediated CTP depletion and erythroid differentiation. Incubation with the pyridinylimidazole p38 MAPK inhibitors, SB203580 or SB220025, suppressed both the CPEC-induced cell cycle arrest and differentiation of K562 cells. SB203580 also prevented the cell cycle arrest and erythroid differentiation of K562 cells induced by Leflunomide (LEF), a non-nucleoside inhibitor of the de novo pyrimidine pathway, without affecting LEF-induced depletion of pyrimidine pools. Finally, selective knockdown of p38 MAPK by using Smart Pool(TM) siRNA to p38 MAPK significantly decreased the CPEC-induced differentiation of K562 cells. These results suggest that endogenous activity of p38 MAP kinases may be required for committing K562 cells to cell cycle arrest and erythroid differentiation under conditions of CTP depletion.