Protection from Cr(VI)-induced malignant cell transformation and tumorigenesis of Cr(VI)-transformed cells by luteolin through Nrf2 signaling
Cr(VI) is a well known environmental carcinogen, but its mechanism of action and the measures required to mitigate its effects remain to be investigated. Our previous studies showed that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) caused malignant transformation, that these transformed cells progressed through tumorigenesis, and that luteolin, a natural compound, inhibited both of these processes. The present study investigates the underlying mechanisms by which luteolin protects cells against Cr(VI)-induced transformation and tumorigenesis. The present study shows that luteolin activates inducible Nrf2 to inhibit Cr(VI)-generated reactive oxygen species (ROS) in normal BEAS-2B cells. The decreased ROS level is likely responsible for the protective effect of luteolin against Cr(VI)-induced malignant cell transformation in normal cells. By contrast, in cells that have been transformed by Cr(VI), Nrf2 is constitutively activated, and its target proteins, heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and superoxide dismutase 1/2 (SOD1/SOD2) are all constitutively activated, and ROS levels are low. Bcl-2, an anti-apoptotic protein and target protein of Nrf2 is elevated. Cr(VI)-transformed BEAS-2B cells develop apoptosis resistance, increasing the survival of these transformed cells. Luteolin decreases interactions between Nrf2 and the antioxidant response element sites of its target anti-apoptotic and antioxidant proteins, Bcl-2, Bcl-XL, and HO-1, which results in decreased constitutive Nrf2 activation. The decreased constitutive Nrf2 activation, decrease in Nrf2 target proteins and consequent apoptosis resistance by luteolin are possible mechanisms that mediate the protective effect of luteolin in Cr(VI)-transformed cells.