title: Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway.
abstract: Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction.
authors.affiliation: First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Shinoda
authors.forename: Muneharu
authors.initials: M
authors.lastname: Maruyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujishita
authors.forename: Junichi
authors.initials: J
authors.lastname: Dohkan
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Oda
authors.forename: Kouichirou
authors.initials: K
authors.lastname: Shinoda
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
authors.forename: Koutarou
authors.initials: K
authors.lastname: Miyabayashi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hayashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawagishi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Shoko
authors.initials: S
authors.lastname: Matsui
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004317:Doxorubicin / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016755:Proto-Oncogene Proteins c-jun; D048051:p38 Mitogen-Activated Protein Kinases; C421109:multidrug resistance-associated protein 1