title: Optimal AraC-Cytotoxicity to AML Cells Requires ERK5 Activity.
abstract: Cytarabine (AraC) has been the primary treatment agent for acute myeloid leukemia (AML) in the past 30 years, but the precise mechanism of its action is not completely known. Here we assessed the role of ERK5 in AraC-induced cell death in AML cell lines HL60 and U937 using ERK5 inhibitors BIX02189 and XMD8-92. We report that inhibition of MEK5/ERK5 activity reduces AraC-induced cell death, DNA damage, the upregulated DNA damage biomarkers, and produced G2 phase cell cycle arrest. In addition, the pro-survival protein P-Bcl2 Ser70 was found to be associated with decreased AraC-induced cell death following XMD8-92 treatment, suggesting a regulatory role of ERK5 on Bcl2 phosphorylation. Our study shows that the full potency of AraC cytotoxicity requires optimal ERK5 activity, suggesting a novel role of ERK5 in cancer chemotherapy. J. Cell. Biochem. 118: 1583-1589, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, 185 South Orange Ave., Newark, New Jersey 07103.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, 185 South Orange Ave., Newark, New Jersey 07103.
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000964:Antimetabolites, Antineoplastic; C000595707:BCL2 protein, human; C533207:BIX 02189; D001570:Benzodiazepinones; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; C568790:XMD 8-92; D003561:Cytarabine; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7
keywords: Bcl2; CELL CYCLE; CYTARABINE (AraC); DNA DAMAGE; ERK5; MITOGEN ACTIVATED PROTEIN KINASES (MAPKs)