Moon Dong-Oh, Park Cheol, Heo Moon-Soo, Park Yeong-Min, Choi Yung Hyun, Kim Gi-Young
Faculty of Applied Marine Science, Cheju National University, Jeju 690-756, South Korea.
Int Immunopharmacol. 2007 Jan;7(1):36-45. doi: 10.1016/j.intimp.2006.08.009. Epub 2006 Sep 8.
MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. Little is known, however, about the effects of cellular and molecular mechanisms on human leukemic U937 cells. In the present study, we found that treatment with PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Thus, our results imply that PD98059-induced apoptosis is significantly involved in down-regulation of Bcl-2, caspase-3 activity, the Akt pathway, and some of the biological functions in U937 cells.
MEK/ERK信号通路在急性髓性白血病中经常被激活，该信号通路的抑制剂使其成为癌症化疗中一个有趣的候选药物。然而，关于细胞和分子机制对人白血病U937细胞的影响知之甚少。在本研究中，我们发现用PD98059处理可通过上调细胞周期蛋白依赖性激酶（Cdk）抑制剂显著阻滞G1期，并在U937细胞中产生凋亡的形态学特征，这与聚（ADP-核糖）聚合酶（PARP）裂解和PLC-γ1降解有关。PD98059还降低了Cdk-2、Cdk-4、细胞周期蛋白D1和细胞周期蛋白E的表达，并增加了有丝分裂抑制剂p16（INIa）、p21（Waf1）和p27（Kip1）的高水平表达。此外，Bcl-2的过表达和半胱天冬酶-3抑制剂z-DEVD-fmk通过下调半胱天冬酶-3活性显著减弱了PD98059诱导的凋亡，但并未减弱G1期阻滞。此外，PD98059下调了Akt磷酸化，并与LY294002联合处理产生了凋亡的协同效应。因此，我们的结果表明，PD98059诱导的凋亡与U937细胞中Bcl-2、半胱天冬酶-3活性、Akt通路的下调以及一些生物学功能显著相关。
