Curcumin activates distinct programming of redox metabolism towards differential regulation of gene expression mediated by Nrf1 and Nrf2

AbstractionCurcumin (CUR), a naturally occurring phenolic small molecule, has been extensively applied in the treatment of diverse diseases for over half a century. Currently, this chemical has also been verified to exhibit a wide array of its biopharmacological activities, such as enhancing immunity, possessing antiviral, anti-cardiovascular, and anti-cancer properties. Besides, also as a nutritional supplement, CUR enables inflammatory prevention and enhance the combined efficacy of it with chemotherapy. Such characteristic of safeguarding normal organisms while treating or alleviating diseases is manifested as a common bidirectional regulation and its hormetin effect of phenolic compounds, particularly in response to stress. In this redox process, two antioxidant transcription factors Nrf1 and Nrf2 (encoded by Nfe2l1 and Nfe2l2, respectively) play distinct and crucial roles. Thereby, we investigated their expression profiles of genes regulated by Nrf1 and Nrf2 in different signaling responses modulated by CUR. The resulting evidence has been provided, demonstrating that distinctive cellular metabolisms, molecular pathways, and signaling mechanisms account for Nrf1 and Nrf2, as drug targets. Both factors also play diverse roles in the anticancer effects of CUR on HepG2 cells and xenograft mice. However, the effect of CUR on xenograft tumors in vivo is not entirely satisfactory, although such anti-cancer effect was achieved by promoting Nrf1 expression, it appeared more reliant on Nrf2 (particularly in the absence of Nrf1). As such, we unexpectedly discovered there is not a simple regulatory relationship between CUR and Nrf2. This is supported by substantial inhibition of Nrf2 by CUR in the aberrantly proliferating Nrf1-/- cells, even albeit this chemical stimulates the expression of Nrf1 and Nrf2 in wild-type cells.