Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells.
Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells.
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发表时间：
2005
影响因子：
2
通讯作者：
V. Golubkov;Agustin Garcia;F. Markland
中科院分区：
文献类型：
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作者：
V. Golubkov;Agustin Garcia;F. Markland
芬维甲酸（4-HPR）是一种合成的类维甲酸，据报道在体外可以抑制癌细胞的生长。材料与方法采用标准技术检测4-HPR对卵巢癌（OVCAR-5）细胞增殖、活力和侵袭的影响。我们还使用免疫细胞化学检测了4-HPR对肌动蛋白细胞骨架的作用，并使用免疫沉淀和磷酸酪氨酸免疫印迹检测了4-HPR对局灶黏附激酶（FAK）磷酸化的作用。然后，我们使用Matrigel上的管形成实验检测了4-HPR在内皮细胞上的活性。结果4-HPR浓度大于1 μ m时，对OVCAR-5细胞增殖和活力有抑制作用，10 μ m时对OVCAR-5细胞生长有70-90%的抑制作用。4-HPR（1微米）可显著抑制OVCAR-5的侵袭。鉴于细胞骨架在细胞运动中的重要性，我们检测了4-HPR对肌动蛋白细胞骨架和FAK磷酸化的作用。在1 mM芬维啶处理3天的OVCAR-5细胞中，肌动蛋白细胞骨架应力纤维被破坏，FAK酪氨酸磷酸化呈剂量依赖性升高。1微米4-HPR处理的内皮细胞不能形成管状，但形成小的细胞聚集体。结论芬维啶通过作用于肌动蛋白骨架和调节FAK酪氨酸磷酸化而具有抗肿瘤活性。4-HPR也抑制内皮细胞管的形成，这是血管生成的一个重要步骤。
BACKGROUND Fenretinide (4-HPR) is a synthetic retinoid that has been reported to inhibit the growth of cancer cell lines in vitro. MATERIALS AND METHODS We examined the effect of 4-HPR on ovarian cancer (OVCAR-5) cell proliferation, viability and invasion using standard techniques. We also examined the action of 4-HPR on the actin cytoskeleton using immunocytochemistry, and on phosphorylation of focal adhesion kinase (FAK) using immunoprecipitation and phosphotyrosine immunoblotting. We then examined the activity of 4-HPR on endothelial cells using the tube formation assay on Matrigel. RESULTS 4-HPR inhibited OVCAR-5 cell proliferation and viability at concentrations higher than 1 microM, with 70-90% growth inhibition at 10 microM. 4-HPR (1 microM) significantly inhibited OVCAR-5 invasion after 3 days preincubation. In view of the importance of the cytoskeleton in cell motility, we examined the action of 4-HPR on the actin cytoskeleton and on FAK phosphorylation. In OVCAR-5 cells treated with 1 mM fenretinide for 3 days, actin cytoskeleton stress fibers were disrupted and FAK tyrosine phosphorylation was elevated dose-dependently. Endothelial cells treated with 1 microM 4-HPR failed to form tubes, but formed small cellular aggregates. CONCLUSION Fenretinide has anti-tumor activity by acting on the actin cytoskeleton and by regulating FAK tyrosine phosphorylation. 4-HPR also inhibits endothelial cell tube formation, a major step in angiogenesis.