Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions
Hypoxia inducible factor-1 influences sensitivity to paclitaxel of human lung cancer cell lines under normoxic conditions
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DOI：
10.1111/j.1349-7006.2007.00537.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Hiraoka, Masahiro
中科院分区：
文献类型：
--
作者：
Zeng, Lihua;Kizaka-Kondoh, Shinae;Hiraoka, Masahiro
紫杉醇（PTX）是一种抗癌药物，可有效对抗多种实体瘤。在原位移植的动物模型中，使用体内成像装置检测PTX对两种人肺癌细胞系PC 14 PE 6和NCI-H441的作用。尽管PTX在NCI-H441中有效抑制肿瘤生长并提高存活率，但其在PC 14 PE 6中不影响这些。体外实验证实，PC 14 PE 6细胞在常氧条件下对PTX具有抗性，并且两种细胞系在缺氧条件下对PTX具有抗性。结果发现，在常氧条件下，PC 14 PE 6细胞中内源性缺氧诱导因子（HIF）-1 α的表达水平远高于NCI-H441细胞。此外，当PC 14 PE 6中HIF-1 α特异性siRNA降低HIF-1 α表达，NCI-H441中外源HIF-1 α基因过表达增加时，这些细胞系对PTX的敏感性逆转。这些结果表明，HIF-1影响这些细胞的PTX敏感性。作者进一步研究了β-微管蛋白，PTX的靶分子，在这些细胞中进行蛋白质印迹和免疫组织化学分析。在常氧和缺氧条件下，这些细胞中β-微管蛋白的表达水平相当，而β-微管蛋白的分布和细胞形态根据HIF-1 α表达水平而改变，表明HIF-1影响微管的构象和动力学。这些数据支持HIF-1靶向方法与PTX组合的潜在发展，其中耐药性往往导致治疗失败。
Paclitaxel (PTX) is an anticancer drug that is effective against a wide range of solid tumors. The effect of PTX on two human lung cancer cell lines, PC14PE6 and NCI-H441 cells, was examined in an orthotopically transplanted animal model with an in vivo imaging devise. Although PTX effectively suppressed tumor growth and improved survival rate in NCI-H441, it did not influence these in PC14PE6. In vitro experiments confirmed that PC14PE6 cells are resistant to PTX under normoxic conditions and that both cell lines were resistant to PTX under hypoxic conditions. It was found that the expression level of endogenous hypoxia inducible factor (HIF)-1 alpha in PC14PE6 is much higher than that in NCI-H441 cells under normoxic conditions. Furthermore, sensitivity to PTX in these cell lines was reversed when HIF-1 alpha expression was decreased by siRNA specific to HIF-1 alpha in PC14PE6 and increased by overexpression of the exogenous HIF-1 alpha gene in NCI-H441. These results suggest that HIF-1 influences the PTX sensitivity of these cells. The authors further examined beta-tubulin, a target molecule of PTX, with western blotting and immunohistochemical analysis in these cells. The expression level of beta-tubulin was comparable in these cells under both normoxic and hypoxic conditions while the distribution of beta-tubulin and cell morphology were changed according to HIF-1 alpha expression levels, suggesting that HIF-1 influences the conformation and dynamics of microtubules. These data support the potential development of HIF-1 targeted approaches in combination with PTX, where drug resistance tends to contribute to treatment failure.