title: Involvement of mitogen-activated protein kinase in signal transducer and activator of transcription-1 mediated differentiation induced by bortezomib in acute myeloid leukemia cells.
abstract: In this paper we report a new myeloid differentiation effect of bortezomib (BTZ) in acute myeloid leukemia (AML) cell lines and primary patient-derived AML cells; this effect was assayed by investigating growth-inhibition, cell morphology, differentiation markers, and nitro-blue tetrazolium reduction. We show that BTZ induces the phosphorylation of several mitogen-activated protein (MAP) kinases, including MEK/ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK. BTZ-induced cell differentiation is almost completely reversed by PD98059, an inhibitor of MEK, which also attenuates the increase in phospho-JNK p46. However, p38 activation does not appear to be required for the differentiation induced by BTZ. Furthermore, the differentiation effect of BTZ is associated with increased protein level of signal transducer and activator of transcription-1 (STAT1), a molecular determinant of myeloid differentiation, due to effects on both its synthesis and degradation. In short, this study reveals that BTZ activates the MEK/ERK cascade, which further up-regulates the expression and activity of the key myeloid transcription factor STAT1, thus promoting myeloid differentiation. These findings contribute to an unexpected potential mechanism for the antitumor activity of BTZ in AML.
authors: Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Xinglu
authors: X
authors: Zhou
authors: Yanfen
authors: Y
authors: Fang
authors: Hui
authors: H
authors: Jing
authors: Like
authors: L
authors: Zhong
authors: Peihua
authors: P
authors: Luo
authors: Hua
authors: H
authors: Song
authors: Bo
authors: B
authors: Yang
authors: Qiaojun
authors: Q
authors: He
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011719:Pyrazines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000069286:Bortezomib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one