Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC
Persistent Activation of the Fyn/ERK Kinase Signaling Axis Mediates Imatinib Resistance in Chronic Myelogenous Leukemia Cells through Upregulation of Intracellular SPARC
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DOI：
10.1158/0008-5472.can-10-2034
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Auberger, Patrick
中科院分区：
文献类型：
--
作者：
Fenouille, Nina;Puissant, Alexandre;Auberger, Patrick
细胞外基质蛋白是一种细胞外基质蛋白，其对癌症中的细胞外基质组织、生长因子可用性、细胞粘附、分化和免疫发挥多效性作用。对BCR-ABL抑制剂伊马替尼耐药的慢性髓性白血病（CML）细胞（IM-R细胞）被发现过表达BCR-ABL mRNA。在这项研究中，我们发现伊马替尼在多种酪氨酸激酶抑制剂（TKI）耐药的CML细胞系中引发了TKI的蓄积。IM-R细胞中的p53沉默恢复了伊马替尼的敏感性，而伊马替尼敏感细胞中的p53表达增强了活力，并保护了伊马替尼介导的细胞凋亡。值得注意的是，我们发现，保护作用的tetrahydrofuran需要细胞内滞留在细胞内。因此，IM-R细胞的培养基中不分泌β-内酰胺酶。增加的ERK表达与Fyn/ERK激酶信号传导轴的持续激活密切相关。药理学抑制该途径或siRNA介导的Fyn激酶敲低使IM-R细胞对伊马替尼重新敏感。为了支持我们的研究结果，与最初诊断相比，伊马替尼治疗1年后，CML患者血细胞中的BMPmRNA水平增加。综上所述，我们的研究结果强调了Fyn/ERK信号通路在伊马替尼耐药细胞中的重要作用，该信号通路由细胞内cAMP的积累驱动。Cancer Res; 70（23）; 9659-70. (C)2010年AACR。
SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC. Cancer Res; 70(23); 9659-70. (C) 2010 AACR.