PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib
PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib
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DOI：
10.1158/0008-5472.can-05-3684
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Ono, Mayumi
中科院分区：
文献类型：
--
作者：
Ueda, Shu-ichi;Basaki, Yuji;Ono, Mayumi
肝细胞癌是世界范围内最常见的肿瘤相关死亡原因之一，目前尚无满意的治疗方法。我们之前曾报道过吉非替尼的抗血管生成作用，这是一种选择性的表皮生长因子受体(EGFR)酪氨酸激酶抑制剂，已成功用于肺癌的治疗。在这项研究中，我们利用体外和体内的肝癌细胞系(HCC3、CBO12C3和AD3)，研究了吉非替尼对肿瘤诱导的血管生成的影响。口服吉非替尼可抑制HCC3和CBO12C3诱导的小鼠背侧气囊模型血管生成，但不抑制AD3诱导的血管生成。吉非替尼对EGF刺激的肝癌细胞产生血管内皮生长因子(VEGF)和趋化因子C-X-C基序配体1(CXCL1)的抑制作用在HCC3和CBO12C3细胞中比在AD3细胞中更明显。EGF促进HCC3和CBO12C3细胞中EGFR、Akt和细胞外信号调节蛋白1/2(ERK1/2)的磷酸化，而促进AD3细胞中EGFR和ERK1/2的磷酸化，但不促进Akt的磷酸化。事实上，在AD3细胞中，Akt在缺乏EGF的情况下被结构性激活。吉非替尼抑制所有三种细胞株Akt的磷酸化，但对AD3细胞的作用约为前者的五倍。AD3细胞中PTEN的浓度约为HCC3和CBO12C3细胞中PTEN浓度的一半。将PTEN小干扰RNA导入HCC3细胞，可降低其对吉非替尼的敏感性，因为吉非替尼对Akt磷酸化及血管内皮生长因子和CXCL1的产生均有抑制作用。综上所述，吉非替尼对肝癌诱导的血管生成的影响依赖于其抑制血管生成因子的产生，可能涉及PTEN/Akt信号通路。
Hepatocellular carcinoma (HCC) is one of the most common tumor-related causes of death worldwide for which there is still no satisfactory treatment. We previously reported the antiangiogenic effect of gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been used successfully to treat lung cancer. In this study, we investigated the effects of gefitinib on tumor-induced angiogenesis by using HCC cell lines (HCC3, CBO12C3, and AD3) in vitro as well as in vivo. Oral administration of gefitinib inhibited angiogenesis induced by HCC3 and CBO12C3, but not by AD3 in the mouse dorsal air sac model. Production of both vascular endothelial growth factor (VEGF) and chemokine C-X-C motif ligand 1 (CXCL1) by EGF-stimulated HCC was more markedly inhibited by gefitinib in HCC3 and CBO12C3 cells than in AD3 cells. EGF stimulated the phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in HCC3 and CBO12C3 cells, whereas EGF stimulated phosphorylation of EGFR and ERK1/2, but not Akt in AD3 cells. In fact, Akt was constitutively activated in the absence of EGF in AD3 cells. Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells. The concentration of PTEN in AD3 cells was about a half that in HCC3 and CBO12C3 cells. Transfection of HCC3 cells with PTEN small interfering RNA reduced their sensitivity to gefitinib in terms of its inhibitory effect on both Akt phosphorylation and the production of VEGF and CXCL1. In conclusion, effect of gefitinib on HCC-induced angiogenesis depends on its inhibition of the production of angiogenic factors, probably involving a PTEN/Akt signaling pathway.