Suppression of NRF2 by photodynamic action to enhance bortezomib-triggered DNA damage for synergistic colorectal cancer therapy

Abstract

Anti-tumor agent bortezomib (BTZ) showed poor efficacy in colorectal cancer (CRC), which is attributed to the high expression of KEAP1-NRF2, an essential anti-oxidative system. Oxidative DNA damage is one of the critical mechanisms by which photodynamic therapy (PDT) induces apoptosis in tumor cells, which can be considered an important tool for early non-invasive treatment of CRC. The present work aims to explore the role and mechanism of PDT synergizing with BTZ in the treatment of CRC. The findings showed slight decrease in cell viability in BTZ-treated CRC cells of SW480 and SW620. KEAP1-NRF2 was highly expressed in CRC as revealed by GEPIA, TIMER databases, and in vitro experiments, conferring antioxidant activity. Further investigation revealed BTZ bound KEAP1, resulting in KEAP1-NRF2 decoupling, which was manifested as downregulation of KEAP1 and upregulation of NRF2. CO-IP test provides in-depth confirmation that BTZ impaired NRF2 ubiquitination. When SW480 and SW620 cells were co-treated with the chlorin e6 (Ce6)-PDT and BTZ, the expression of NRF2 was reduced with increased ROS generation and enhanced DNA damage. The combination of PDT and BTZ exhibited robust anti-CRC efficacy, characterized by increased apoptosis in SW480 and SW620 cells and dramatic inhibition of tumor growth in SW480 cell-bearing mice. To summarize, Ce6-mediated PDT combined with BTZ suppresses NRF2 and thus enhances DNA damage against CRC. The present study uncovered the molecular mechanism of redox in CRC and recommends an effective intervention strategy with PDT.