title: Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2529, Riyadh, 11461, Kingdom of Saudi Arabia.
authors.forename: Zaid H
authors.initials: ZH
authors.lastname: Maayah
authors.forename: Mohamed A M
authors.initials: MA
authors.lastname: El Gendy
authors.forename: Ayman O
authors.initials: AO
authors.lastname: El-Kadi
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D061986:MCF-7 Cells; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D000077210:Sunitinib; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; D011758:Pyrroles; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D003609:Dactinomycin; D019363:Cytochrome P-450 CYP1A1; D011505:Protein-Tyrosine Kinases; D000077185:Resveratrol; D000077210:Sunitinib