title: p38 MAPK/PP2Acα/TTP pathway on the connection of TNF-α and caspases activation on hydroquinone-induced apoptosis.
abstract: This study investigated tumor necrosis factor-α (TNF-α)-mediated death pathway contribution to hydroquinone (HQ) cytotoxicity in human leukemia U937 cells. HQ-induced apoptosis of human leukemia U937 cells was characterized by the increase in mitochondrial membrane depolarization, procaspase-8 degradation and tBid production. Downregulation of Fas-associated death domain protein (FADD) blocked HQ-induced procaspase-8 degradation and rescued the viability of HQ-treated cells, suggesting the involvement of a death receptor-mediated pathway in HQ-induced cell death. HQ induced increased TNF-α mRNA stability led to TNF-α protein expression upregulation, whereas HQ suppressed TNF-α-mediated NFκB pathway activation. HQ elicited protein phosphatase 2A catalytic subunit α (PP2Acα) upregulation via p38 mitogen-activated protein kinase (MAPK)-mediated CREB/c-Jun/ATF-2 phosphorylation, and PP2Acα upregulation was found to promote tristetraprolin (TTP) degradation. Suppression of p38 MAPK activation and protein phosphatase 2A (PP2A) activity abrogated TNF-α upregulation and procaspase degradation in HQ-treated cells. Overexpression of TTP suppressed HQ-induced TNF-α upregulation and restored the viability of HQ-treated cells. Moreover, TTP overexpression increased TNF-α mRNA decay in HQ-treated cells. Taken together, our data indicate that HQ elicits TNF-α upregulation via p38 MAPK/PP2A-mediated TTP downregulation, and suggest that the TNF-α-mediated death pathway is involved in HQ-induced U937 cell death. The same pathway was also proven to be involved in the HQ-induced death of human leukemia HL-60 and Jurkat cells.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Liu
authors.forename: Wen-Min
authors.initials: WM
authors.lastname: Chou
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D007938:Leukemia; D053078:Membrane Potential, Mitochondrial; D016328:NF-kappa B / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051816:Tristetraprolin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; D051023:BH3 Interacting Domain Death Agonist Protein; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D006873:Hydroquinones; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497552:ZFP36 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; D053181:Caspase 8; C031927:hydroquinone