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: Wen-Hsin Liu, Wen-Min Chou, Long-Sen Chang
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 4 Pg. 818-27 (Apr 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23288922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 2
• BH3 Interacting Domain Death Agonist Protein
• FADD protein, human
• Fas-Associated Death Domain Protein
• Hydroquinones
• NF-kappa B
• RNA, Messenger
• RNA, Small Interfering
• Tristetraprolin
• Tumor Necrosis Factor-alpha
• ZFP36 protein, human
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• PPP2CA protein, human
• Protein Phosphatase 2
• Caspase 8
• hydroquinone

Topics

• Activating Transcription Factor 2 (genetics)
• Apoptosis
• BH3 Interacting Domain Death Agonist Protein (biosynthesis)
• Caspase 8 (genetics, metabolism)
• Cell Line, Tumor
• Down-Regulation
• Fas-Associated Death Domain Protein (genetics, metabolism)
• Humans
• Hydroquinones (pharmacology)
• JNK Mitogen-Activated Protein Kinases (genetics)
• Leukemia
• Membrane Potential, Mitochondrial
• NF-kappa B (metabolism)
• Protein Phosphatase 2 (metabolism)
• RNA Interference
• RNA, Messenger
• RNA, Small Interfering
• Signal Transduction
• Tristetraprolin (metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• U937 Cells
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)