Photodynamic therapy-triggered nuclear translocation of berberine from mitochondria leads to liver cancer cell death

Abstract

Berberine, a traditional Chinese herbal compound, is known for its broad range of biological activities, including anticancer and phototoxic effects. However, the precise mechanisms underlying its phototoxicity in liver cancer cells remain unclear. In this study, we investigated the potential of berberine as a photosensitizer for photodynamic therapy (PDT) by examining its phototoxic effects under blue light irradiation (488 nm). The results showed that berberine rapidly translocated from the mitochondria to the nucleus upon light exposure, ultimately inducing cell death in SNU449 and Huh7 cells. Additionally, we observed a significant increase in reactive oxygen species, linking the phototoxic effects to oxidative stress. EdU/DAPI staining further revealed a marked reduction in DNA replication, with a complete absence of SNU449 cells in the S phase, indicating cell cycle arrest following treatment with berberine and PDT. Transcriptomic analysis also showed extensive gene expression changes, with GO enrichment indicating altered chromatin accessibility and cellular stress response following berberine and PDT combination therapy. qPCR and Western blotting confirmed that ER stress was significantly induced, triggering the activation of the pro-apoptotic protein DDIT3, which contributes to berberine-PDT-induced cell death. These findings underscore the potential of berberine as a photosensitizer and provide a promising approach for enhancing liver cancer treatment using PDT.

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Funding

Shenzhen Natural Science Fund,(20220810151804002); Innovative Research Group Project of the National Natural Science Foundation of China(82273291); Sanming Project of Medicine in Shenzen Municipality(SZSM202003009); HaiYa Young Scientist Foundation of Shenzhen University General Hospital,(2024-HY008)