Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells
Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells
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DOI：
10.1016/j.toxicon.2007.08.015
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发表时间：
2008-01-01
期刊：
影响因子：
2.8
通讯作者：
Kim, Gi-Young
中科院分区：
文献类型：
--
作者：
Moon, Dong-Oh;Park, Sung-Yong;Kim, Gi-Young
蜂毒肽（Melittin，MEL）是蜂毒（Bee venom，BV）中的一种主要多肽，具有抑制肿瘤细胞增殖和诱导肿瘤细胞凋亡的作用。然而，MEL诱导细胞凋亡的分子机制尚未完全阐明，特别是在人类白血病细胞中。在本研究中，我们报告MEL诱导白血病U937细胞凋亡，通过下调Akt信号通路。此外，MEL诱导的细胞凋亡伴随着Bcl-2的下调和caspase-3的激活。凋亡的诱导也伴随着凋亡抑制蛋白（IAP）家族蛋白的下调。用半胱天冬酶-3抑制剂z-DEVD-fetamine处理U937细胞能够显著恢复MEL处理的细胞中的细胞活力。此外，在MEL处理的Bel-2过表达的U937细胞中，caspase-3介导的凋亡反应显著减弱。这些结果表明Bcl-2的下调在MEL暴露后caspase-3的活化中起主要作用。MEL还引发Akt的下调。LY 294002（Akt的抑制剂）显著降低细胞活力，并增加具有亚G1期DNA含量的细胞比例。结果表明，MEL诱导的人白血病U937细胞凋亡的关键调节因子包括Bcl-2和caspase-3，它们通过Akt信号通路控制。(C)2007爱思唯尔有限公司保留所有权利。
Melittin (MEL), a major polypeptide in bee venom (BV), is known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in MEL-induced apoptosis have not been fully elucidated, especially in human leukemic cells. In the present study, we report that MEL induces apoptosis in leukemic U937 cells through downregulating Akt signal pathways. Furthermore, MEL-induced apoptosis was accompanied by downregulation of Bcl-2 and activation of caspase-3. The induction of apoptosis also was accompanied by the downregulation of the inhibitor of apoptosis protein (IAP) family proteins. Treatment of U937 cells with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in MEL-treated cells. Additionally, the caspase-3 mediated apoptotic response was significantly attenuated in Bel-2-overexpressing U937 cells treated with MEL. These results indicate that downregulation of Bcl-2 plays a major role in activation of caspase-3 following MEL exposure. MEL also triggered downregulation of Akt. LY294002 (an inhibitor of Akt) significantly decreased cell viability and increased the proportion of cells with sub-G1 phase DNA content. The results indicated that key regulators in MEL-induced apoptosis in human leukemic U937 cells include Bcl-2 and caspase-3, which are controlled through the Akt signaling pathway. (C) 2007 Elsevier Ltd. All rights reserved.