PI3K/Akt
Pathway Mediates Nrf2/ARE Activation in Human
L02 Hepatocytes Exposed to Low-Concentration HBCDs
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Abstract
We investigated the effects of hexabromocyclododecanes
(HBCDs)
at environmentally relevant concentrations on human L02 hepatocytes
and explored possible underlying molecular mechanism(s), focusing
on functional interactions between the phosphatidylinositol 3-kinase/protein
kinase B (PI3K/Akt) and nuclear factor-erythroid 2-related factor
2/antioxidant response element (Nrf2/ARE) pathways. The results showed
that low concentrations of HBCDs could stimulate cell proliferation
in a “DNA-dependent protein kinase catalytic subunit”
(DNA-PKcs)-dependent manner, increase protein levels and nuclear translocation
of transcription factor Nrf2, and upregulate expression of its target
gene heme oxygenase-1 (HO-1). Electrophoretic mobility-shift assays
(EMSAs) showed that ARE was a prominent element for HO-1 induction
after low-concentration HBCDs exposure. The relationship between PI3K/Akt
pathway and Nrf2/HO-1 axis was demonstrated by the finding that pretreatment
with PI3K inhibitors (wortmannin, LY294002) attenuated the upregulation
of Nrf2 expression induced by HBCDs exposure. Furthermore, knock-down
of DNA-PKcs through small interfering RNA blocked Nrf2/HO-1 axis activation
in L02 cells exposed to low-concentration HBCDs. Moreover, DNA-PKcs
and phosphorylated Akt at Ser<sup>473</sup> proved to be crucial in
regulating the Nrf2-ARE pathway. Thus, the PI3K/Akt pathway is essential
in regulating Nrf2-ARE pathway activation in L02 cells induced by
low-concentration HBCDs