title: The Association Between p38 MAPK-Mediated TNF-α/TNFR2 up-Regulation and 2-(4-Aminophenyl)-7-Methoxybenzothiazole-Induced Apoptosis in Human Leukemia U937 Cells.
abstract: The primary cause of treatment failures in acute myeloid leukemia is usually associated with defects in the apoptotic pathway. Several studies suggest that 2-(4-aminophenyl)-7-methoxybenzothiazole (7-OMe-APBT) may potentially induce apoptosis of cancer cells. Thus, the present study was conducted to explore the cytotoxic effect of 7-OMe-APBT on human leukemia U937 cells. The apoptosis of human leukemia U937 cells induced by 7-OMe-APBT was characterized by an increase in mitochondrial membrane depolarization, procaspase-8 degradation, and tBid production. Down-regulation of FADD blocked 7-OMe-APBT-induced procaspase-8 degradation and rescued the viability of 7-OMe-APBT-treated cells, suggesting the involvement of a death receptor-mediated pathway in 7-OMe-APBT-induced cell death. Increased TNF-α expression, TNFR2 expression, and p38 MAPK phosphorylation were noted in 7-OMe-APBT-treated cells. Pretreatment with a p38 MAPK inhibitor abolished 7-OMe-APBT-induced TNF-α and TNFR2 up-regulation. 7-OMe-APBT stimulated p38 MAPK/c-Jun-mediated transcriptional up-regulation of TNFR2, while the increased TNF-α mRNA stability led to TNF-α up-regulation in 7-OMe-APBT-treated cells. Treatment with 7-OMe-APBT up-regulated protein phosphatase 2A catalytic subunit α (PP2Acα) expression via the p38 MAPK/c-Jun/ATF-2 pathway, which, in turn, promoted tristetraprolin (TTP) degradation. Pretreatment with a protein phosphatase 2A inhibitor or TTP over-expression abrogated TNF-α up-regulation in 7-OMe-APBT-treated cells. Abolishment of TNF-α up-regulation or knock-down of TNFR1/TNFR2 by siRNA restored the viability of 7-OMe-APBT-treated cells. Taken together, our data indicate a connection between p38 MAPK-mediated TNF-α and TNFR2 up-regulation and 7-OMe-APBT-induced TNF-α-mediated death pathway activation in U937 cells. The same pathway also elucidates the mechanism underlying 7-OMe-APBT-induced death of human leukemia HL-60 cells.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Laboratory Medicine Division, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Chao
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Jung-Jung
authors.initials: JJ
authors.lastname: Changchien
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Hu
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.|Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C000604236:2-(4-aminophenyl)-7-methoxybenzothiazole; D000814:Aniline Compounds; D052160:Benzothiazoles; D034741:RNA, Small Interfering; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases