Luteolin induces oxidative stress and apoptosis via dysregulating the cytoprotective Nrf2-Keap1-Cul3 redox signaling in metastatic castration-resistant prostate cancer cells.

backgroundThe treatment of metastatic castration-resistant prostate cancer (mCRPC) is still challenging clinically. Due to the refractor and highly metastatic phenotype of mCRPC, novel therapy strategies need to be investigated. Luteolin, a promising anticancer agent with various biological targets in many cancer types, also has a pro-oxidant effect that selectively triggers ROS and apoptosis. In recent years, among its ROS-mediated mechanisms, the inhibitory effect of luteolin on the nuclear factor-E2-related factor 2 (Nrf2), the main ROS scavenger protein in cancer cells, has been reported. However, no evidence exists that luteolin potentially regulates the Nrf2 or its regulator signaling pathway, Nrf2-Keap1-Cul3 axis, concerning its pro-oxidant effects associated with ROS-triggered apoptosis in any PCa cells or tumor model. METHODS AND

resultsIn the present study, we investigated for the first time whether the anticancer effect of luteolin is associated with pro-oxidant activity via the regulation of the Nrf2-Keap1-Cul3 redox signaling in PC3 and DU145 mCRPC cells. The results showed that luteolin significantly caused more cytotoxic, apoptotic, and pro-oxidant effects in a dose-dependent manner in mCRPC cells than in WPMY-1 normal prostate fibroblast cells for 72 h. Moreover, significant inhibition of Nrf2-Keap1-Cul3 redox signaling has occurred in response to increasing doses of luteolin in mCRPC cells.

conclusionsThe current study put forth the potential pro-oxidant inhibitory effect of luteolin on the Nrf2-Keap1-Cul3 axis in mCRPC cells for the first time. Thus, luteolin might be an attractive therapy strategy with an inhibitory effect on the cytoprotective Nrf2-Keap1-Cul3 redox signaling for treating mCRPC.