1. Upregulation of ABCG2 by romidepsin via the aryl hydrocarbon receptor pathway.
- Author
-
To KK, Robey R, Zhan Z, Bangiolo L, and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters genetics, Acetylation drug effects, Aryl Hydrocarbon Receptor Nuclear Translocator metabolism, Cell Line, Tumor, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Metabolic Networks and Pathways genetics, Neoplasm Proteins genetics, Promoter Regions, Genetic genetics, Receptors, Aryl Hydrocarbon antagonists & inhibitors, Receptors, Aryl Hydrocarbon metabolism, Up-Regulation genetics, ATP-Binding Cassette Transporters biosynthesis, Antibiotics, Antineoplastic pharmacology, Depsipeptides pharmacology, Histone Deacetylase Inhibitors pharmacology, Neoplasm Proteins biosynthesis, Receptors, Aryl Hydrocarbon agonists, Response Elements
- Abstract
Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line-specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics., (©2011 AACR.)
- Published
- 2011
- Full Text
- View/download PDF