Curcumin-induced GADD153 upregulation: modulation by glutathione.

As we reported previously, GADD153 is upregulated in colon cancer cells exposed to curcumin. In the present study, we ascertained the involvement of glutathione and certain sulfhydryl enzymes associated with signal transduction in mediating the effect of curcumin on GADD153. Curcumin-induced GADD153 gene upregulation was attenuated by reduced glutathione (GSH) or N-acetylcysteine (NAC) and potentiated by the glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). Additionally, GSH and NAC decreased the intracellular content of curcumin. Conversely, curcumin decreased intracellular glutathione and also increased the formation of reactive oxygen species (ROS) in cells, but either GSH or NAC prevented both of these effects of curcumin. In affecting the thiol redox status, curcumin caused activation of certain sulfhydryl enzymes involved in signal transduction linked to GADD153 expression. Curcumin increased the expression of the phosphorylated forms of PTK, PDK1, and PKC-delta, which was attenuated by either GSH or NAC and potentiated by BSO. Furthermore, selective inhibitors of PI3K and PKC-delta attenuated curcumin-induced GADD153 upregulation. Collectively, these findings suggest that a regulatory thiol redox-sensitive signaling cascade exists in the molecular pathway leading to induction of GADD153 expression as caused by curcumin.