Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5
Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5
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DOI：
10.1158/0008-5472.can-06-1377
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发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Carter, Christopher
中科院分区：
文献类型：
--
作者：
Liu, Li;Cao, Yichen;Carter, Christopher
据报道，通过RAF/丝裂原活化蛋白/细胞外信号调节激酶（ERK）激酶(NIEK)/ERK级联的血管生成和信号传导在肝细胞癌的发展中起重要作用。Sorafenib （BAY 43-9006, Nexavar）是一种多激酶抑制剂，具有抗Raf激酶和几种酪氨酸激酶受体的活性，包括血管内皮生长因子受体2，血小板衍生生长因子受体（PDGFR）， （NIEGFR2）。FLT3， Bet和c-Kit。在本研究中，我们研究了索拉非尼对PLC/PRF/5和HepG2肝癌细胞的体外作用，以及对PLC/PRF/5人类肿瘤异种移植严重联合免疫缺陷小鼠的体内抗肿瘤效果和作用机制。索拉非尼抑制了这两种细胞系中NIEK和ERK的磷酸化，下调了cyclin D1的水平。Sorafenib还降低了eIF4E的磷酸化水平，并以不依赖MEK/ erk的方式下调抗凋亡蛋白mci - 1。与MEK/ erk依赖性和MEK/ erk非依赖性信号通路的作用一致，索拉非尼抑制了两种HCC细胞系的增殖并诱导了细胞凋亡。在PLC/PRF/5异种移植模型中，剂量为10 mg/kg的tosylate索拉非尼抑制肿瘤生长49%。在30 mg/kg剂量下，索拉非尼tosylate产生完全的肿瘤生长抑制。剂量为100 mg/kg时，50%的小鼠肿瘤部分消退。在作用机制研究中，索拉非尼抑制ERK和eIF4E的磷酸化，减少微血管面积（通过CD34免疫组化评估），诱导肿瘤细胞凋亡（通过末端脱氧核苷酸转移酶介导的缺口末端标记评估）。这些结果表明索拉非尼在HCC模型中的抗肿瘤活性可能归因于抑制肿瘤血管生成（VEGFR和PDGFR）和直接影响肿瘤细胞增殖/存活（Raf激酶信号依赖和信号独立机制）。
Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal- regulated kinase (ERK) kinase (NIEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas HCC. Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine k-mases, including vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor (PDGFR), (NIEGFR2). FLT3, Bet, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/ PRF/5 human tumor xenografts in severe combined immuno-deficient mice. Sorafenib inhibited the phosphorylation of NIEK and ERK and down-regrulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein McI-I in a MEK/ ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signalingdependent and signaling-independent mechanisms).