Suppression of Survivin Induced by a BCR-ABL/JAK2/STAT3 Pathway Sensitizes Imatinib-Resistant CML Cells to Different Cytotoxic Drugs
Suppression of Survivin Induced by a BCR-ABL/JAK2/STAT3 Pathway Sensitizes Imatinib-Resistant CML Cells to Different Cytotoxic Drugs
复制标题
DOI：
10.1158/1535-7163.mct-12-0550
复制
发表时间：
2013-06-01
影响因子：
5.7
通讯作者：
Vigneri, Paolo
中科院分区：
文献类型：
--
作者：
Stella, Stefania;Tirro, Elena;Vigneri, Paolo
慢性粒细胞白血病（CML）的BCR-ABL癌蛋白显示出独特的细胞质定位和组成型酪氨酸激酶活性，导致不同途径的激活，有利于细胞增殖和存活。BCR-ABL在RNA和蛋白水平诱导survivin表达，从而抑制CML细胞的凋亡机制，并有助于白血病克隆的扩增。我们报道，在人CML细胞系中，BCR-ABL介导的生存素上调涉及JAK 2/STAT 3通路，因为沉默任一蛋白质都会导致生存素表达的一致性降低。由于BCR-ABL基因扩增而对甲磺酸伊马替尼（IM）无反应的细胞系在生存素下调后对药物不敏感。然而，由于BCR-ABL激酶结构域中的点突变而对IM不敏感的细胞在生存素沉默后对羟基脲（HU）高度反应。为了解决我们的研究结果可能的临床应用，我们使用了shepherdin，一种细胞渗透性的肽模拟化合物，通过阻止其与Hsp 90的相互作用来下调生存素的表达。与Shepherdin孵育的永生化细胞系对IM敏感和抵抗增强HU和阿霉素诱导的细胞死亡。同样，Shepherdin与第一代和第二代酪氨酸激酶抑制剂的组合降低了来自IM敏感和IM耐药CML患者的人类祖细胞的集落形成潜力。这些结果表明，旨在降低生存素水平的策略可能是对IM无反应的CML患者的潜在治疗选择。(C)2013年AACR。
The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) displays exclusive cytoplasmic localization and constitutive tyrosine kinase activity leading to the activation of different pathways that favor cell proliferation and survival. BCR-ABL induces survivin expression at both them RNA and protein level, thus inhibiting the apoptotic machinery of CML cells and contributing to the expansion of the leukemic clone. We report that, in human CML cell lines, BCR-ABL-mediated upregulation of survivin involves the JAK2/STAT3 pathway since silencing of either protein caused a consistent reduction in survivin expression. Cell lines unresponsive to imatinib mesylate (IM) because of BCR-ABL gene amplification were not resensitized to the drug after survivin downregulation. However, cells insensitive to IM because of point mutations in the BCR-ABL kinase domain were highly responsive to hydroxyurea (HU) after survivin silencing. To address the possible clinical applications of our results, we used shepherdin, a cell-permeable peptidomimetic compound that downregulates survivin expression by preventing its interaction with Hsp90. Incubation with shepherdin of immortalized cell lines both sensitive and resistant to IM enhanced cell death induced by HU and doxorubicin. Similarly, the combination of shepherdin with first-and second-generation tyrosine kinase inhibitors reduced the colony-forming potential of human progenitors derived from both patients with IMsensitive and IM-resistant CML. These results suggest that strategies aimed at reducing survivin levels may represent a potential therapeutic option for patients with CML unresponsive to IM. (C) 2013 AACR.