title: Low-dose anisomycin sensitizes glucocorticoid-resistant T-acute lymphoblastic leukemia CEM-C1 cells to dexamethasone-induced apoptosis through activation of glucocorticoid receptor and p38-MAPK/JNK.
abstract: Glucocorticoid (GC) resistance in children with acute lymphoblastic leukemia (ALL) usually resulted in the failure of treatment. Exploring new agents to overcome GC resistance is important. Here we reported for the first time that low-dose anisomycin has the potential to sensitize GC-resistant T-ALL CEM-C1 cells to dexamethasone (DEX). Compared with the use of DEX or low-dose anisomycin alone, co-treatment with them resulted in a significant increase of growth inhibition, apoptosis and cell cycle arrest in CEM-C1 cells through induction of activated caspase-3 and up-regulation of Bim, p21and p27, and down-regulation of Mcl-1, Bcl-2, c-myc, cyclin A and cyclin D1. Furthermore, co-treatment remarkably activated glucocorticoid receptor (GR), p38-MAPK and JNK, and all of them were canceled only by the GR inhibitor RU486, indicating GR might be an at the upstream of GR-p38-MAPK/JNK pathway. We conclude that low-dose anisomycin sensitizes GC-resistant CEM-C1 cells to DEX and this effect is mediated, at least in part, by activation of the GR-p38-MAPK/JNK signaling pathway.
authors.affiliation: Department of Pediatric Hematology and Immunology.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jiao
authors.initials: J
authors.lastname: Ge
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Guo
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.forename: Zhi-Gui
authors.initials: ZG
authors.lastname: Ma
authors.forename: Xi-Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Zhu
mesh_terms: D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D000841:Anisomycin; D003907:Dexamethasone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Anisomycin; JNK; acute lymphoblastic leukemia (ALL); glucocorticoid receptor; glucocorticoid resistance; p38-MAPK