Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation
Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation
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DOI：
10.1007/s00204-012-0996-y
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发表时间：
2013-05-01
影响因子：
6.1
通讯作者：
Korashy, Hesham M.
中科院分区：
文献类型：
--
作者：
Maayah, Zaid H.;El Gendy, Mohamed A. M.;Korashy, Hesham M.
舒尼替尼（SUN）是一种新型多靶点口服酪氨酸激酶抑制剂，具有抗血管生成和抗肿瘤活性。然而，文献中报道的SUN对哺乳动物细胞中细胞色素P450 1A 1（CYP 1A 1）基因组成型表达的影响的信息仍不清楚。因此，本研究的主要目的是研究SUN诱导人乳腺癌MCF 7细胞CYP 1A 1基因表达的可能性，并探讨其分子机制。我们的研究结果表明，SUN诱导MCF 7细胞CYP 1A 1 mRNA，蛋白和活性水平在浓度依赖性的方式。由SUN引起的CYP 1A 1 mRNA的增加被转录抑制剂放线菌素D完全阻断;这意味着SUN增加了从头RNA合成。此外，SUN增加荧光素酶报告基因表达的能力表明，芳烃受体（AhR）依赖的转录控制，并排除任何转录后机制的可能性。此外，白藜芦醇，一种众所周知的AhR拮抗剂，阻断AhR激活，阻止了SUN诱导的CYP 1A 1基因表达，进一步证实了AhR的参与。有趣的是，这与SUN不能直接结合并诱导胞质AhR在体外转化为其DNA结合形式有关，表明SUN的作用不涉及与AhR的直接结合。目前的手稿提供了SUN通过AhR配体非依赖性机制诱导MCF 7细胞中CYP 1A 1基因表达的能力的第一个证据。
Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.