Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.
Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.
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DOI：
10.1158/1535-7163.mct-08-0138
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发表时间：
2008-11
影响因子：
5.7
通讯作者：
Jove R
中科院分区：
文献类型：
--
作者：
Yang F;Van Meter TE;Buettner R;Hedvat M;Liang W;Kowolik CM;Mepani N;Mirosevich J;Nam S;Chen MY;Tye G;Kirschbaum M;Jove R
髓母细胞瘤是儿童最常见的恶性脑肿瘤。索拉非尼（Nexavar，BAY 43 -9006）是一种多激酶抑制剂，在多种肿瘤细胞中阻断细胞增殖并诱导细胞凋亡。索拉非尼在两个已建立的人髓母细胞瘤细胞系（Daoy和D283）和原代培养物（VC 312）中抑制增殖并诱导凋亡。此外，索拉非尼抑制两种细胞系和原发性肿瘤细胞中信号转导和转录激活因子3（STAT 3）的磷酸化。磷酸化STAT 3（Tyr 705）的抑制以剂量和时间依赖性方式发生。相反，AKT（蛋白激酶B）仅在D283和VC 312髓母细胞瘤细胞中降低，并且在这些细胞中，索拉非尼B不抑制MAPK（ERK 1/2）。索拉非尼可下调D型细胞周期蛋白（D1、D2、D3）和E型细胞周期蛋白。此外，抗凋亡蛋白Mcl-1（Bcl-2家族成员）的表达降低，并与索拉非尼诱导的细胞凋亡相关。最后，索拉非尼在小鼠异种移植模型中抑制人髓母细胞瘤细胞的生长。总之，我们的数据表明，索拉非尼阻断STAT 3信号传导以及细胞周期和凋亡调节蛋白的表达，与髓母细胞瘤中细胞增殖的抑制和细胞凋亡的诱导相关。这些发现为索拉非尼治疗儿童髓母细胞瘤提供了理论依据。
Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multi-kinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in both cell lines and the primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr705) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and MAPKs (ERK1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the anti-apoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data demonstrate that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.