Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

被引:40
作者
Dong, Yucui [1 ,3 ]
Jia, Limin [1 ,3 ]
Wang, Xiaohua [1 ,3 ]
Tan, Xiaoqing [1 ,3 ]
Xu, Jiankai [2 ]
Deng, Zhenling [1 ,3 ]
Jiang, Tao [4 ]
Rainov, Nikolai G. [5 ]
Li, Baoxin [6 ]
Ren, Huan [1 ,3 ]
机构
[1] Harbin Med Coll, Dept Immunol, Harbin 150081, Peoples R China
[2] Harbin Med Coll, Coll Bioinformat, Harbin 150081, Peoples R China
[3] Immun & Infect Key Lab Heilongjiang Prov, Harbin 150081, Peoples R China
[4] Beijing Tiantan Hosp, Inst Neurosurg, Beijing 100005, Peoples R China
[5] Klinikum Augsburg, Dept Neurosurg, D-86156 Augsburg, Germany
[6] Harbin Med Coll, Dept Pharmacol, Harbin 150081, Peoples R China
基金
美国国家科学基金会;
关键词
glioblastoma; imatinib mesylate; extracellular signal-regulated kinase; tyrosine kinase inhibitor; cell signaling pathways; targeted therapy; PROTEIN-KINASE INHIBITORS; BRAIN-TUMOR CONSORTIUM; GROWTH-FACTOR PDGF; TARGETED THERAPIES; PHASE-II; MESYLATE; GLIOBLASTOMA; AUTOCRINE; RECURRENT; AGENTS;
D O I
10.3892/ijo.2010.861
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Clinical studies using the tyrosine kinase inhibitor, imatinib mesylate (Gleevec (R)), in glioblastoma, have shown no major inhibition of tumor growth or extension of survival for patients, unlike those in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The molecular mechanisms of action of imatinib in glioblastoma cells are still not well understood. In this study, we investigated the effects of imatinib on the platelet derived growth factor receptor (PDGFR) downstream signaling pathways as well as on other cellular functions in human glioblastoma cells. NIH3T3 fibroblast and K562 CML cells were used for comparison. Western blot analysis demonstrated that imatinib was more effective in inhibiting the activated rather than the quiescent forms of the target proteins. Furthermore, the imatinib treatment induced the sustained activation of extracellular signal-regulated kinase (ERK 1/2) signaling as well as components of other downstream signaling pathways, such as PI3K/Akt, STAT3 and p38MAPK. Prior stimulation of the malignant cells with exogenous PDGF-BB partially abrogated this activation. Further analysis indicated that the activation of ERK induced by the imatinib treatment was related to the S-phase re-entry of the cell cycle in one of the three glioma cells. Imatinib significantly inhibited cell migration but not cell growth. The combination treatment of imatinib with a MEK or PI3K inhibitor resulted in significant growth inhibition but did not inhibit cell migration beyond the inhibition achieved with the imatinib treatment alone. The treatment of glioma cells with small interfering RNA inhibiting PDGFRB, however, evoked enhanced Akt signaling. These results indicate that the imatinib treatment of malignant glioma does not result in significant inhibitory effects and should be used with caution.
引用
收藏
页码:555 / 569
页数:15
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