Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor.
Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of platelet-derived growth factor receptor and transactivation of epidermal growth factor receptor.
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DOI：
10.1158/1535-7163.mct-08-0889
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
MacDonald TJ
中科院分区：
文献类型：
--
作者：
Abouantoun TJ;MacDonald TJ
血小板衍生生长因子受体（PDGFR）表达与转移性髓母细胞瘤相关。PDGF刺激成神经管细胞瘤细胞磷酸化Erk并促进迁移。我们试图确定阻断PDGFR活性是否有效抑制成神经管细胞瘤细胞迁移和侵袭所需的信号。我们分别用甲磺酸伊马替尼（Gleevec®），一种PDGFR酪氨酸激酶抑制剂，或用siRNA转染PDGFRB来检测阻断PDGFR磷酸化和表达的效果。测量PDGFR - bb刺激后PDGFR细胞的信号传导、迁移、侵袭、存活和增殖，无论是否抑制PDGFR。PDGF-BB处理细胞后，PDGFRB、Akt和Erk磷酸化升高，EGFR反激活，与细胞迁移、存活和增殖增强相关。伊马替尼（1 μ m）处理D556细胞，分别在24 h和48 h抑制PDGF-BB和血清介导的迁移和侵袭，同时抑制PDGF-BB对PDGFRB、Akt和Erk的激活，但诱导PTEN的表达和活性增加。伊马替尼治疗也在72 h诱导DAOY细胞凋亡，48 h抑制DAOY和D556细胞增殖，siRNA沉默PDGFRB同样抑制信号传导、迁移和存活，siRNA和伊马替尼治疗均抑制pdgf - bb介导的EGFR反活化，表明伊马替尼治疗的作用是特异性的PDGFRB靶点抑制。这些结果表明PDGFRB酪氨酸激酶活性对髓母细胞瘤细胞的迁移和侵袭至关重要，可能通过反激活EGFR，因此伊马替尼可能是治疗髓母细胞瘤的重要新型药物。
Platelet-derived growth factor receptor (PDGFR) expression correlates with metastatic medulloblastoma. PDGF stimulation of medulloblastoma cells phosphorylates Erk and promotes migration. We sought to determine whether blocking PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion. DAOY and D556 human medulloblastoma cells were treated with imatinib mesylate (Gleevec®), a PDGFR tyrosine kinase inhibitor, or transfected with siRNA to PDGFRB to test the effects of blocking PDGFR phosphorylation and expression, respectively. PDGFR cell signaling, migration, invasion, survival and proliferation following PDGF-BB stimulation, with and without PDGFR inhibition, were measured. PDGF-BB treatment of cells increased PDGFRB, Akt and Erk phosphorylation, and transactivated EGFR, which correlated with enhanced migration, survival and proliferation. Imatinib (1 uM) treatment of DAOY and D556 cells inhibited PDGF-BB- and serum-mediated migration and invasion at 24 h and 48 h, respectively, and concomitantly inhibited PDGF-BB activation of PDGFRB, Akt and Erk, but induced increased PTEN expression and activity. Imatinib treatment also induced DAOY cell apoptosis at 72 h and inhibited DAOY and D556 cell proliferation at 48 h. siRNA silencing of PDGFRB similarly inhibited signaling, migration and survival and both siRNA and imatinib treatment inhibited PDGF-BB-mediated EGFR transactivation, indicating that the effects of imatinib treatment are specific to PDGFRB target inhibition. These results indicate that PDGFRB tyrosine kinase activity is critical for migration and invasion of medulloblastoma cells, possibly by transactivating EGFR, and thus imatinib may represent an important novel therapeutic agent for the treatment of medulloblastoma.