Antlsperger Dorothee S M, Dirsch Verena M, Ferreira Dulce, Su Jen-Liang, Kuo Ming-Liang, Vollmar Angelika M
Department of Pharmacy, Center of Drug Research, University of Munich, Germany.
Oncogene. 2003 Jan 30;22(4):582-9. doi: 10.1038/sj.onc.1206161.
Treatment of human promyeloleukemic HL-60 cells with the experimental antileukemic drug ajoene induces the activation of the mitogen-activated protein kinases (MAPKs) c-Jun NH(2)-terminal kinase (JNK), p38 and extracellular signal-regulated kinases (ERK) 1/2 as well as the survival kinase Akt. JNK activation occurred in HL-60/neo, HL-60/bcl-x(L), and in HL-60 cells pretreated with the pan-caspase inhibitor zVAD-fmk, indicating that JNK activation is not dependent on ajoene-induced mitochondria perturbation and subsequent caspase activation. Cells overexpressing a dominant-negative JNK showed no altered sensitivity towards ajoene suggesting that the activation of JNK is not necessary for ajoene-induced cell death. Inhibition of p38 MAPK by SB 203580 had no influence on ajoene-mediated apoptosis. In contrast, inhibition of ERK1/2 vastly enhanced ajoene-induced cell death. The survival kinase Akt, in contrast, did not participate in ajoene-induced death signaling as shown by the use of the phosphatidylinositol-3-kinase inhibitor wortmannin. Thus in contrast to the previous findings regarding stress-induced cell death, ajoene-mediated activation of JNK and p38 has no impact on ajoene-induced apoptosis in HL-60 cells. Blockade of ERK1/2 but not Akt pathways leads to sensitization of cells against ajoene-mediated apoptosis supporting the view that inhibition of ERK1/2 is a valuable strategy to increase the sensitivity of promyeloleukemic cells towards ajoene.
用实验性抗白血病药物大蒜素处理人早幼粒白血病HL-60细胞，可诱导丝裂原活化蛋白激酶（MAPK）c-Jun氨基末端激酶（JNK）、p38和细胞外信号调节激酶（ERK）1/2以及存活激酶Akt的激活。JNK激活发生在HL-60/neo、HL-60/bcl-x(L)以及用泛半胱天冬酶抑制剂zVAD-fmk预处理的HL-60细胞中，这表明JNK激活不依赖于大蒜素诱导的线粒体扰动及随后的半胱天冬酶激活。过表达显性负性JNK的细胞对大蒜素的敏感性未改变，这表明JNK激活对于大蒜素诱导的细胞死亡并非必需。用SB 203580抑制p38 MAPK对大蒜素介导的凋亡没有影响。相反，抑制ERK1/2可极大地增强大蒜素诱导的细胞死亡。相比之下，如使用磷脂酰肌醇-3-激酶抑制剂渥曼青霉素所示，存活激酶Akt不参与大蒜素诱导的死亡信号传导。因此，与先前关于应激诱导细胞死亡所发现的结果相反，大蒜素介导的JNK和p38激活对HL-60细胞中大蒜素诱导的凋亡没有影响。阻断ERK1/2而非Akt途径会导致细胞对大蒜素介导的凋亡敏感化，这支持了抑制ERK1/2是增加早幼粒白血病细胞对大蒜素敏感性的一种有价值策略的观点。
