Dihydrotanshinone I inhibits ovarian tumor growth by activating oxidative stress through Keap1-mediated Nrf2 ubiquitination degradation

作者：Chengtao Sun, Bing Han, Yufei Zhai, Huan Zhao, Xuan Li, Jun Qian, Xiaolong Hao, Qun Liu, Jiayan Shen, Guoyin Kai · 发表于：Free Radical Biology and Medicine · 年份：2022 · DOI：10.1016/j.freeradbiomed.2022.01.015 · 被引用次数：66 · 研究领域：Genomics, phytochemicals, and oxidative stress、Plant-derived Lignans Synthesis and Bioactivity、Ferroptosis and cancer prognosis

Dihydrotanshinone I (DHT), a bioactive compound in Salvia miltiorrhiza, was reported to exhibit cytotoxicity against various malignancies. However, the underlying mechanism on ovarian cancer remains unclear. Here, DHT inhibited cell viability of ovarian cancer HO8910PM, SKOV3, A2780 and ES2 cells. It showed moderate inhibitory effect on ovarian epithelial IOSE80 cells and lower toxicity than chemotherapy drugs. DHT induced apoptosis and G2 cell cycle arrest accompanied by reduced expression of Bcl-2, Caspase-3, and increased Bax. Meanwhile, DHT increased ROS accumulation, decreased mitochondrial membrane potential and activated oxidative stress in HO8910PM and ES2 cells. Mechanistically, DHT inhibited Nrf2 and p62 expression, Nrf2 target genes and enzymes, and Nrf2 nuclear translocation, while increased the expression of Nrf2 inhibitor Keap1. NAC, a ROS scavenger, rescued DHT-induced proliferation inhibition, ROS generation and Nrf2 inhibition. DHT alleviated tBHQ-induced Nrf2 expression and increased its mRNA level. However, the proteasome inhibitor MG132 blocked DHT-induced Nrf2 inhibition, suggesting a post-translational regulation manner. DHT enhanced Nrf2 binding with Keap1, leading to potentiated Nrf2 ubiquitination degradation. Furthermore, Nrf2 and p62 overexpression blocked DHT-induced Nrf2 and p62 inhibition. Consistent with the in vitro results, DHT significantly delayed tumor growth in HO8910PM and ES2 xenograft nude mice, decreased tumor marker HE4 and CA125 leve...