Xiang Yu, Chen Xiaying, Wang Wengang, Zhai Lijuan, Sun Xueni, Feng Jiao, Duan Ting, Zhang Mingming, Pan Ting, Yan Lili, Jin Ting, Gao Quan, Wen Chengyong, Ma Weirui, Liu Wencheng, Wang Deqiang, Wu Qibiao, Xie Tian, Sui Xinbing
School of Pharmacy and Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China.
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.
Front Pharmacol. 2021 Oct 29;12:775506. doi: 10.3389/fphar.2021.775506. eCollection 2021.
Erianin, a natural product derived from , 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. , 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.
毛萼乙素是一种从[来源未提及]中提取的天然产物，已被证明在多种癌症中具有抗肿瘤活性。然而，毛萼乙素在膀胱癌细胞中的作用及其分子机制仍未被探索。在本研究中，我们发现毛萼乙素可引发膀胱癌细胞死亡和细胞周期停滞。随后我们证明，毛萼乙素可促进致死性脂质基活性氧（ROS）的积累以及谷胱甘肽（GSH）的消耗，提示其诱导了铁死亡。在进一步的研究中，铁死亡抑制剂去铁胺（DFO）、N-乙酰半胱氨酸（NAC）和GSH可挽救毛萼乙素导致的细胞死亡，而坏死性凋亡抑制剂necrostatin-1、氯喹（CQ）或Z-VAD-FMK则不能，这表明铁死亡在毛萼乙素导致的细胞死亡中起主要作用。此外，我们还表明毛萼乙素通过诱导铁死亡抑制肿瘤生长。机制上，我们证明核因子E2相关因子2（NRF2）失活是毛萼乙素诱导铁死亡的关键决定因素。在膀胱癌细胞中，NRF2激活剂叔丁基对苯二酚（TBHQ）可抑制毛萼乙素诱导的铁死亡。然而，使用短发夹RNA抑制NRF2可增强毛萼乙素处理诱导的铁死亡反应。总之，我们的数据首次证明毛萼乙素可在膀胱癌中引发铁死亡样细胞死亡和脂质过氧化，有望成为一种有前景的治疗膀胱癌的抗癌化合物。
