Involvement of mitogen‐activated protein kinase in signal transducer and activator of transcription‐1 mediated differentiation induced by bortezomib in acute myeloid leukemia cells
Involvement of mitogen‐activated protein kinase in signal transducer and activator of transcription‐1 mediated differentiation induced by bortezomib in acute myeloid leukemia cells
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DOI：
10.1002/mc.20873
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发表时间：
2013-01
影响因子：
4.6
通讯作者：
Xing-lu Zhou;Yan-fen Fang;Hui Jing;Like Zhong;P. Luo;Hua Song;Bo Yang;Qiaojun He
中科院分区：
文献类型：
--
作者：
Xing-lu Zhou;Yan-fen Fang;Hui Jing;Like Zhong;P. Luo;Hua Song;Bo Yang;Qiaojun He
本文报道了硼替佐米(BTZ)对急性髓系白血病(AML)细胞系和原代患者来源的AML细胞的一种新的髓系分化作用；通过观察生长抑制、细胞形态、分化标志物和硝基蓝四氮唑还原来检测这种作用。我们发现BTZ可诱导几种丝裂原活化蛋白(MAP)的磷酸化，包括MEK/ERK、c-Jun氨基末端激酶(JNK)和p38MAPK。MEK的抑制剂PD98059几乎完全逆转了BTZ诱导的细胞分化，这也减弱了磷酸化JNK p46的增加。然而，BTZ诱导分化似乎并不需要p38的激活。此外，BTZ的分化作用与信号转导和转录激活因子-1(STAT1)的蛋白水平升高有关，STAT1是髓系分化的分子决定因素，通过影响其合成和降解。总之，本研究揭示了BTZ激活了MEK/ERK级联反应，进一步上调了关键的髓系转录因子STAT1的表达和活性，从而促进了髓系分化。这些发现为BTZ在AML中的抗肿瘤活性提供了一个意想不到的潜在机制。©2011 Wiley期刊，Inc.
In this paper we report a new myeloid differentiation effect of bortezomib (BTZ) in acute myeloid leukemia (AML) cell lines and primary patient‐derived AML cells; this effect was assayed by investigating growth‐inhibition, cell morphology, differentiation markers, and nitro‐blue tetrazolium reduction. We show that BTZ induces the phosphorylation of several mitogen‐activated protein (MAP) kinases, including MEK/ERK, c‐Jun N‐terminal kinase (JNK), and p38 MAPK. BTZ‐induced cell differentiation is almost completely reversed by PD98059, an inhibitor of MEK, which also attenuates the increase in phospho‐JNK p46. However, p38 activation does not appear to be required for the differentiation induced by BTZ. Furthermore, the differentiation effect of BTZ is associated with increased protein level of signal transducer and activator of transcription‐1 (STAT1), a molecular determinant of myeloid differentiation, due to effects on both its synthesis and degradation. In short, this study reveals that BTZ activates the MEK/ERK cascade, which further up‐regulates the expression and activity of the key myeloid transcription factor STAT1, thus promoting myeloid differentiation. These findings contribute to an unexpected potential mechanism for the antitumor activity of BTZ in AML. © 2011 Wiley Periodicals, Inc.