Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3
Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3
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DOI：
10.1038/labinvest.3700348
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发表时间：
2005-12-01
影响因子：
5
通讯作者：
Wasik, MA
中科院分区：
文献类型：
--
作者：
Marzec, M;Kasprzycka, M;Wasik, MA
ALK酪氨酸激酶作为与核磷蛋白（NPM）和其他伴侣嵌合的蛋白质的异常表达在T淋巴细胞和其他细胞的恶性细胞转化中起关键作用。在这里，我们报告说，两个小分子，结构相关，喹唑啉型化合物，WHI-131和WHI-154，直接抑制NPM/ALK的酶活性，通过体外激酶试验证明，使用合成的富含酪氨酸的寡肽和激酶本身作为底物。NPM/ALK活性的抑制导致恶性T细胞抑制其生长、诱导凋亡和抑制STAT 3的酪氨酸磷酸化，STAT 3是NPM/ALK诱导的肿瘤发生的关键效应物。我们还表明，STAT 3酪氨酸磷酸化在恶性T细胞中由NPM/ALK介导，不依赖于Jak 3激酶，如在不表达可检测的Jak 3的NPM/ALK转染的BaF 3细胞中以及在Jak 3活性被pan-Jak或Jak 3选择性抑制剂削弱或Jak 3表达被Jak 3 siRNA废除的NPM/ALK阳性恶性T细胞中存在STAT 3磷酸化所证明的。上述结果代表了关于ALK酶活性作为T细胞淋巴瘤和以活性形式表达激酶的其他恶性肿瘤中有吸引力的治疗靶点的“原理验证”实验。
Aberrant expression of the ALK tyrosine kinase as a chimeric protein with nucleophosmin (NPM) and other partners plays a key role in malignant cell transformation of T-lymphocytes and other cells. Here we report that two small-molecule, structurally related, quinazoline-type compounds, WHI-131 and WHI-154, directly inhibit enzymatic activity of NPM/ALK as demonstrated by in vitro kinase assays using a synthetic tyrosine-rich oligopeptide and the kinase itself as the substrates. The inhibition of NPM/ALK activity resulted in malignant T cells in suppression of their growth, induction of apoptosis and inhibition of tyrosine phosphorylation of STAT3, the key effector of the NPM/ALK-induced oncogenesis. We also show that the STAT3 tyrosine phosphorylation is mediated in the malignant T cells by NPM/ALK independently of Jak3 kinase as evidenced by the presence of STAT3 phosphorylation in the NPM/ALK-transfected BaF3 cells that do not express detectable Jak3 and in the NPM/ALK- positive malignant T cells with either Jak3 activity impaired by a pan-Jak or Jak3-selective inhibitor or Jak3 expression abrogated by Jak3 siRNA. The above results represent the 'proof-of-principle' experiments with regard to the ALK enzymatic activity as an attractive therapeutic target in T-cell lymphomas and other malignancies that express the kinase in an active form.