Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways.
Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways.
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DOI：
10.1158/1541-7786.mcr-09-0220
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Yang F;Jove V;Xin H;Hedvat M;Van Meter TE;Yu H
髓母细胞瘤是儿童最常见的恶性脑肿瘤。舒尼替尼是一种口服多靶点酪氨酸激酶抑制剂，在临床试验中用作癌症治疗的抗血管生成剂。在这篇报道中，我们证明了舒尼替尼诱导人髓母细胞瘤短期原代培养细胞(VC312)和已建立的人髓母细胞瘤细胞系(DAOY)的凋亡和抑制细胞增殖。经舒尼替尼处理后，caspase-3激活，PARP裂解，促凋亡基因Bak和Bim表达上调，抗凋亡蛋白Survivin表达受抑。舒尼替尼还下调了细胞周期蛋白E、D2和D3的表达，上调了参与细胞周期调控的p21Cip1的表达。此外，它还抑制肿瘤细胞中信号转导和转录激活因子3(STAT3)和蛋白激酶B(AKT)的磷酸化。Sunitinib诱导的STAT3(Tyr705)去磷酸化是通过降低JAK2和Src的活性来实现的。此外，蛋白酪氨酸磷酸酶的抑制剂钒酸钠部分阻断了苏尼替尼对磷酸化STAT3的抑制作用。在舒尼替尼治疗后，伴随着下游蛋白、GSK-3β和mTOR的磷酸化减少。组成性激活的STAT3突变体或肉豆蔻酰化AKT的表达部分阻断了舒尼替尼在这些肿瘤细胞中的作用。孙尼替尼在体外也能抑制髓母细胞瘤细胞的迁移。这些发现表明，舒尼替尼可能用于儿童髓母细胞瘤的治疗。
Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we demonstrate that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of PARP, and upregulation of pro-apoptotic genes, Bak and Bim, as well as inhibiting expression of survivin, an anti-apoptotic protein. Sunitinib treatment also down-regulated cyclin E, D2 and D3, and up-regulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. De-phosphorylation of STAT3 (Tyr705) induced by sunitinib was contributed by a reduction in activities of JAK2 and Src. Additionally, sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of phosphorylated AKT after sunitinib treatment was accompanied by decreased phosphorylation of downstream proteins, GSK-3β and mTOR. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor cells in vitro. These findings suggest that potential use of sunitinib for treatment of pediatric medulloblastomas.