title: Decreased expression of nucleophosmin/B23 increases drug sensitivity of adriamycin-resistant Molt-4 leukemia cells through mdr-1 regulation and Akt/mTOR signaling.
abstract: Nucleophosmin/B23 (NPM) is a nuclear protein with prosurvival and ribosomal RNA processing functions. However, the potential role of NPM involved in drug-resistance in leukemia has not been investigated clearly. In this study, we generated an adriamycin (ADM)-resistant lymphoblastic cell line Molt-4/ADR (MAR) by stepwise induction. Cell proliferation, sensitivity to chemotherapy agents and expressions of drug resistance related molecules were assessed. The IC50 of Molt-4 cells were 0.58±0.11μmol/L and MAR cells were 22.56±1.94μmol/L, meaning MAR cells were 38.63 fold resistant to Molt-4 cells. Furthermore, MAR cells gained an expression of mdr-1 (P-gp) and a higher expression of NPM compared to Molt-4 cells. Knockdown of NPM by RNA interference (RNAi) suppressed the viability of both Molt-4 and MAR cells. After NPM RNAi, the IC50 of MAR and Molt-4 cells were 3.83±0.38μmol/L and 0.19±0.02μmol/L respectively. Both of them revealed an increase of drug sensitivity with down-regulation of mdr-1 and Akt/mTOR signaling. Knockdown of mdr-1 could also reverse the drug resistance, with no change in NPM expression. It could be concluded that knockdown of NPM reversed the drug resistance by down-regulating P-gp and Akt/mTOR signal pathway, indicating that NPM may serve as a potential modulator in drug resistance.
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Buyuan
authors.initials: B
authors.lastname: Chen
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Minhui
authors.initials: M
authors.lastname: Lin
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Xinji
authors.initials: X
authors.lastname: Chen
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Liu
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China. Electronic address: jdhu@medmail.com.cn.
authors.forename: Jianda
authors.initials: J
authors.lastname: Hu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000090243:Nucleophosmin; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000090243:Nucleophosmin; D004317:Doxorubicin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Acute lymphoblastic leukemia; Multidrug resistance; Nucleophosmin/B23; P-gp; PI3K/Akt; RNA interference