title: Influence of proteasome inhibitor bortezomib on the expression of multidrug resistance genes and Akt kinase activity.
abstract: The goal of this work was to study the mechanisms of ABC family transport proteins' regulation by a new-generation antitumor drug - the proteasome inhibitor bortezomib (Velcade). ABC transporters determine the multidrug resistance of tumor cells (MDR). We confirmed our previously discovered observation that bortezomib affects the expression of genes involved in the formation of MDR (ABCB1 gene, also known as MDR1, and ABCC1-MRP1), reducing the amount of their mRNA. This effect was found to depend on Akt kinase activity: the Akt activity inhibitor Ly 294002 increased the amount of MRP1 mRNA in KB 8-5 cells. It was also shown that bortezomib increased the amount of Akt kinase phosphorylated form in cell lines of malignant cells KB 8-5 and K 562/i-S9 that overexpressed ABCB1 transporter (Pgp), and did not affect the amount of activated Akt in the corresponding wild-type cells. When exposed to bortezomib, selection of resistant to it cell variants was much faster for a Pgp-overexpressing cell population (compared to wild-type cells). It is shown that bortezomib affects the amount of MRP1 gene mRNA, relocating the multifunctional protein YB-1, dependent on Akt activity, from cytoplasm to nuclei of MCF-7 breast cancer cells. The data indicate that the transcriptional activity of YB-1 might be one of the mechanisms that determine the effect of bortezomib on the amount of MRP1 gene mRNA.
authors.affiliation: Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia. panlidia@gmail.com
authors.forename: L A
authors.initials: LA
authors.lastname: Panischeva
authors.forename: E S
authors.initials: ES
authors.lastname: Kakpakova
authors.forename: E Y
authors.initials: EY
authors.lastname: Rybalkina
authors.forename: A A
authors.initials: AA
authors.lastname: Stavrovskaya
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001897:Boronic Acids; D000069286:Bortezomib; D004791:Enzyme Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D051840:Y-Box-Binding Protein 1; C513055:ABCB1 protein, human; C070856:YBX1 protein, human; C421109:multidrug resistance-associated protein 1