Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile.
Depsipeptide (FK228), a histone deacetylase inhibitor, is a promising new anticancer agent. The mechanism of resistance to this agent was studied using KU812 cells. Depsipeptide-resistant KU812 cells expressed P-glycoprotein (P-gp) and their resistance was abolished by co-treatment with verapamil. P-gp expression returned to the parental cell level when resistant cells were cultured in depsipeptide-free medium, while resistant cells cultured in the medium containing 16 nM depsipeptide still showed hyper-acetylation of histones. Moreover, resistant cells showed erythroid differentiation. Microarray analysis revealed that 28 genes showed increased expression and three genes showed decreased expression in resistant cells compared with parental cells. These 31 genes had various functions relating to signal transduction, cell cycle, apoptosis, and control of cell morphology and differentiation. Among the 28 genes that were upregulated, 15 genes also showed an increased expression in parental cells treated with 4 nM depsipeptide for 48 h, while the other 13 genes including P-gp were different. Among the three genes with decreased expression, HEP27 was most dramatically downregulated. These findings suggest that continuous exposure to depsipeptide reversibly induces P-gp, which contributes to the onset of resistance, but the altered gene expression profile of resistant cells may also play a role.
Yamada
Hisashi
H
Department of Molecular Genetics, Institute of DNA Medicine, Jikei University School of Medicine, Nishi-Shinbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan. hyamad@jikei.ac.jp
Arakawa
Yasuhiro
Y
Saito
Shinobu
S
Agawa
Miyuki
M
Kano
Yasuhiko
Y
Horiguchi-Yamada
Junko
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000107:Acetylation / Q000187:drug effects; D000426:Alcohol Dehydrogenase / Q000096:biosynthesis; D000429:Alcohol Oxidoreductases; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000074409:Carbonyl Reductase (NADPH); D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D006657:Histones; D009687:Nuclear Proteins; C087123:romidepsin; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D000074409:Carbonyl Reductase (NADPH); C095961:DHRS2 protein, human