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The cytoprotective effect of butin against oxidative stress is mediated by the up‐regulation of manganese superoxide dismutase expression through a PI3K/Akt/Nrf2‐dependent pathway
Author(s) -
Zhang Rui,
Chae Sungwook,
Lee Jun Hwa,
Hyun Jin Won
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24068
Subject(s) - oxidative stress , protein kinase b , pi3k/akt/mtor pathway , superoxide dismutase , gene knockdown , reactive oxygen species , chemistry , sod2 , microbiology and biotechnology , signal transduction , biology , apoptosis , biochemistry
Butin (7,3′,4′‐trihydroxydihydroflavone), a flavonoid with antioxidant activity, was recently reported to protect cells against H 2 O 2 ‐induced apoptosis, oxidative DNA damage and oxidative mitochondrial dysfunction. The objective of the present study was to elucidate the mechanism by which butin protects mitochondria. The antioxidant function of manganese superoxide dismutase (Mn SOD) is important in preventing oxidative stress. While exposure to H 2 O 2 reduced the expression of Mn SOD in Chinese hamster lung fibroblast (V79‐4), the addition of butin restored Mn SOD expression at both the mRNA and protein levels, resulting in increased Mn SOD activity. The transcription factor NF‐E2‐related factor 2 (Nrf2) regulates Mn SOD gene expression by binding to the antioxidant responsive element (ARE). Butin enhanced the nuclear translocation and ARE‐binding activity of Nrf2, which was decreased by H 2 O 2 . The siRNA‐mediated knockdown of Nrf2 attenuated butin‐induced Mn SOD expression and activity. Further, phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB, Akt) contributed to the ARE‐driven Mn SOD expression. Butin activated PI3K/Akt and exposure to either LY294002 (a PI3K inhibitor), Akt inhibitor IV (an Akt‐specific inhibitor), or Akt siRNA suppressed the butin‐induced activation of Nrf2, resulting in decreased Mn SOD expression and activity. Finally, the cytoprotective effect of butin against H 2 O 2 ‐induced cell damage was suppressed by the siRNA‐mediated knockdown of Mn SOD. These studies demonstrate that butin attenuates oxidative stress by activating Nrf2‐mediated Mn SOD induction via the PI3K/Akt signaling pathway. J. Cell. Biochem. 113: 1987–1997, 2012. © 2012 Wiley Periodicals, Inc.