Paraquat toxicity is attenuated by 4-phenylbutyrate-induced phosphorylation of ERK2 via PI3K in A549 cells
著者
保科, 千里
(Hoshina, Chisato)
上位タイトル
Biochemical and biophysical research communications
Vol.503,
No.2
(2018.
9)
,p.809-
814
識別番号
ISSN
0006-291X
DOI
10.1016/j.bbrc.2018.06.080
その他
PMID：29913144
博士論文情報
学位授与番号
10107B476
学位授与年月日
2018-12-25
学位名
博士（医学）
学位授与機関
旭川医科大学
抄録
Paraquat (PQ) is a widely used herbicide in the world despite being highly toxic to humans. PQ causes fatal damage to multiple organs, especially the lungs. While oxidative stress is the main toxic mechanism of PQ, there is no established standard therapy for PQ poisoning. In this study, we investigated the cytoprotective effect of 4-phenylbutyrate (4PBA) on PQ toxicity in human lung adenocarcinoma A549 cells. Phosphorylation levels of major survival signaling kinases Akt and ERK, as well as expression levels of antioxidant enzymes catalase and superoxide dismutase 2 (SOD2) were examined. The cytoprotective mechanism of 4PBA against PQ was compared with the antioxidant reagent trolox. We demonstrated that both 4PBA and trolox attenuated PQ toxicity, but their mechanisms were different. 4PBA increased ERK2 phosphorylation levels, which could be inhibited by the PI3K inhibitor LY294002. The cytoprotective effect of 4PBA was also inhibited by LY294002. Catalase expression levels were increased by 4PBA, although this increase was not inhibited by LY294002. 4PBA did not increase SOD2 expression. Trolox did not affect phosphorylation of Akt or ERK, or the expression of antioxidant enzymes. These results suggest that 4PBA attenuated PQ cytotoxicity by ERK2 activation via PI3K. Our study may provide new findings for understanding the molecular mechanism underlying cytoprotection by 4PBA, as well as new therapeutic targets for PQ poisoning.
