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

Abstract

Background: The 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 results: In 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. Conclusions: The 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.