日本毒性学会学術年会
第44回日本毒性学会学術年会
セッションID: P-277
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一般演題 ポスター
Reactive oxygen species produced from 9,10-phenanthrenequinone activate epidermal growth factor receptor signaling through oxidative modification of protein tyrosine phosphatase 1B
*Nho Cong LUONGYumi ABIKOYoshito KUMAGAI
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 Redox regulation through cysteine modification of proteins involves in maintaining intracellular homeostasis. Protein tyrosine phosphatases (PTPs) negatively regulate EGFR, which regulates cell survival. Once PTPs undergo oxidation through cysteine, EGFR is eventually phosphorylated and transmits the phosphorylation signal to downstream proteins such as ERK1/2. Reactive oxygen species (ROS) produced in vivo are potentially expected to activate the signaling through S-oxidation of PTPs. 9,10-Phenanthrenequinone (9,10-PQ), contaminated in diesel exhaust particles, is a ROS producer through the redox cycling by interacting with electron donors in cells. These suggest that 9,10-PQ might be an EGFR activator through oxidative modification of PTPs such as PTP1B. Here, we examined that this speculation about 9,10-PQ-mediated activation of EGFR signaling in A431 cells and contribution of the signal transduction to its cytotoxicity.
 Exposure of 9,10-PQ to A431 cells activated EGFR-ERK1/2 signaling, coupled to the decrease of cellular PTP activity. ROS produced through the redox cycling of 9,10-PQ in A431 cells were abolished by pretreatment of polyethylene glycol conjugated with catalase (PEG-CAT), a ROS scavenger. Under this condition, PEG-CAT markedly inhibited the 9,10-PQ-mediated activation of EGFR-ERK1/2 signaling. Furthermore, 9,10-PQ-dependent inhibition of recombinant hPTP1B was not observed during incubation of 9,10-PQ with CAT. Nano UPLC-MSE analysis revealed that 9,10-PQ oxidized PTP1B at Cys215. Interestingly, an EGFR inhibitor enhanced cytotoxicity of 9,10-PQ, indicating that EGFR-ERK1/2 activation is a cytoprotective response to its toxicity. Collectively, these results suggested that 9,10-PQ-produced ROS activate EGFR-ERK1/2 signaling, at least in part, as a cellular defense system against 9,10-PQ presumably through oxidative modification of PTP1B.

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