Department of Pharmacology, Wuhan University, Wuhan, China.
Cancer Chemother Pharmacol. 2011 Sep;68(3):619-29. doi: 10.1007/s00280-010-1521-8. Epub 2010 Dec 1.
Cytochrome P450 (CYP) ω-hydroxylase, mainly consisting of CYP4A and CYP4F, converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) that induces angiogenic responses in vivo and in vitro. The present study examined the role of CYP ω-hydroxylase in angiogenesis and metastasis of human non-small cell lung cancer (NSCLC).
The effect of WIT003, a stable 20-HETE analog, on invasion was evaluated using a modified Boyden chamber in three NSCLC cell lines. A549 cells were transfected with CYP4A11 expression vector or exposed to CYP ω-hydroxylase inhibitor (HET0016) or 20-HETE antagonist (WIT002), and then ω-hydroxylation activity toward arachidonic acid and the levels of matrix metalloproteinases (MMPs) and VEGF were detected. The in vivo effects of CYP ω-hydroxylase were tested in established tumor xenografts and an experimental metastasis model in athymic mice.
Addition of WIT003 or overexpression of CYP4A11 with an associated increase in 20-HETE production significantly induced invasion and expression of VEGF and MMP-9. Treatment of A549 cells with HET0016 or WIT002 inhibited invasion with reduction in VEGF and MMP-9. The PI3 K or ERK inhibitors also attenuated expression of VEGF and MMP-9. Compared with control, CYP4A11 transfection significantly increased tumor weight, microvessel density (MVD), and lung metastasis by 2.5-fold, 2-fold, and 3-fold, respectively. In contrast, WIT002 or HET0016 decreased tumor volume, MVD, and spontaneous pulmonary metastasis occurrences.
CYP ω-hydroxylase promotes tumor angiogenesis and metastasis by upregulation of VEGF and MMP-9 via PI3 K and ERK1/2 signaling in human NSCLC cells.
细胞色素 P450（CYP）ω-羟化酶主要由 CYP4A 和 CYP4F 组成，将花生四烯酸转化为 20-羟二十碳四烯酸（20-HETE），在体内和体外诱导血管生成反应。本研究探讨了 CYP ω-羟化酶在人非小细胞肺癌（NSCLC）血管生成和转移中的作用。
使用改良 Boyden 室评估稳定的 20-HETE 类似物 WIT003 对三种 NSCLC 细胞系侵袭的影响。用 CYP4A11 表达载体转染 A549 细胞或用 CYP ω-羟化酶抑制剂（HET0016）或 20-HETE 拮抗剂（WIT002）处理，然后检测 ω-羟化酶对花生四烯酸的活性和基质金属蛋白酶（MMPs）和 VEGF 的水平。在已建立的肿瘤异种移植物和裸鼠实验性转移模型中测试 CYP ω-羟化酶的体内作用。
添加 WIT003 或过表达 CYP4A11 导致 20-HETE 产生增加，显著诱导侵袭和 VEGF 和 MMP-9 的表达。用 HET0016 或 WIT002 处理 A549 细胞可抑制侵袭，减少 VEGF 和 MMP-9 的表达。PI3 K 或 ERK 抑制剂也减弱了 VEGF 和 MMP-9 的表达。与对照组相比，CYP4A11 转染使肿瘤重量、微血管密度（MVD）和肺转移分别增加 2.5 倍、2 倍和 3 倍。相比之下，WIT002 或 HET0016 降低了肿瘤体积、MVD 和自发性肺转移发生率。
CYP ω-羟化酶通过人 NSCLC 细胞中 PI3 K 和 ERK1/2 信号通路上调 VEGF 和 MMP-9 促进肿瘤血管生成和转移。
