Abstract
Selenium has been shown to reduce the risk of several forms of human cancer. However, the mechanisms underlying its chemopreventive effects remain largely unresolved. In the present study, we found that methylseleninic acid (MSeA), a monomethylated selenium derivative, induced expression of NQO-1, an important cytoprotection enzyme against oxidative and electrophilic stresses. Nrf2 through interaction with antioxidant response element (ARE), induces expression of many antioxidant enzymes. MSeA treatment resulted in an increased nuclear translocation, subsequent ARE binding and transactivation of Nrf2. Silencing Nrf2 using dominant negative Nrf2 or Nrf2 siRNA markedly reduced the MSeA-induced NQO-1 expression. Moreover, MSeA treatment induced expression of NQO-1 to a much less extent in Nrf2-/- MEF than in Nrf2+/+ MEF. Furthermore, MSeA reduced the level of Keap1, a repressor of Nrf2, at a post-translational level. Ubiquitination of Keap1 was markedly increased in cells exposed to MSeA, which resulted in decreased steady-state levels of Keap1 in parallel with inhibition of keap1-dependent ubiquitination of Nrf2. In addition, Oral administration of MSeA (1 mg/kg) by gavage to mice also induced NQO-1 protein expression in the liver. Methylselenol generated from selenomethionine (SeMet) by methioninase (METase) activity induced expression of NQO-1. In contrast to the treatment with SeMet and METase, SeMet itself failed to induce NQO-1 expression, suggesting that methylselenol, not its metabolite, is directly responsible for NQO-1 induction. Taken together, these results suggest that MSeA, the immediate precursor of methylselenol, upregulates the expression of NQO-1 via the Keap1-Nrf2 signaling, preferentially by targeting cysteine thiol(s) present in Keap1.
