Natural Product Erianin Inhibits Bladder Cancer Cell Growth by Inducing Ferroptosis via NRF2 Inactivation

Yu Xiang; Xiaying Chen; Wengang Wang; Lijuan Zhai; Xueni Sun; Jiao Feng; Ting Duan; Mingming Zhang; Ting Pan; Lili Yan; Ting Jin; Quan Gao; Chengyong Wen; Weirui Ma; Wencheng Liu; Deqiang Wang; Qibiao Wu; Tian Xie; Xinbing Sui

doi:10.3389/fphar.2021.775506

Natural Product Erianin Inhibits Bladder Cancer Cell Growth by Inducing Ferroptosis via NRF2 Inactivation

Front Pharmacol. 2021 Oct 29:12:775506. doi: 10.3389/fphar.2021.775506. eCollection 2021.

Authors

Yu Xiang^{1

2}, Xiaying Chen^{1

2}, Wengang Wang³, Lijuan Zhai⁴, Xueni Sun^{1

2}, Jiao Feng^{1

2}, Ting Duan^{1

2}, Mingming Zhang^{1

2}, Ting Pan^{1

2}, Lili Yan^{1

2}, Ting Jin^{1

2}, Quan Gao^{1

2}, Chengyong Wen^{1

2}, Weirui Ma^{1

2}, Wencheng Liu^{1

2}, Deqiang Wang⁵, Qibiao Wu⁶, Tian Xie^{1

3

2}, Xinbing Sui^{1

2

5

6}

Affiliations

¹ School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China.
² Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.
³ College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
⁴ Zhejiang Chinese Medical University, Hangzhou, China.
⁵ Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China.
⁶ State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.

Abstract

Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.

Keywords: Erianin; bladder cancer; ferroptosis; natural product; nuclear factor E2-related factor 2.