Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation

摘要: 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 effects of SUN constitutive expression cytochrome P450 1A1 (CYP1A1) gene cells from mammalian species remains unclear. Therefore, main objectives current work were to investigate potentiality induce CYP1A1 human breast cancer MCF7 explore molecular mechanisms involved. Our results showed induced mRNA, protein, activity levels concentration-dependent manner cells. The increase mRNA by was completely blocked transcriptional inhibitor, actinomycin D; implying increased de novo RNA synthesis. Furthermore, ability luciferase reporter suggests an aryl hydrocarbon receptor (AhR)-dependent control excludes possibility any posttranscriptional mechanisms. In addition, blocking AhR activation resveratrol, well-known antagonist, prevented SUN-induced expression, further confirms involvement AhR. Interestingly, this associated with inability directly bind transformation cytosolic its DNA-binding form vitro, suggesting effect does not involve direct binding manuscript provides first evidence for through ligand-independent