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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01371

RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer

 Ruonan Zhang1, Haoming Lin2, Shuiping Liu1, Ting Duan1, Lijuan Zhai1, Mingming Zhang1, Xuemeng Han1, Yu Xiang1, Xingxing Huang1, Tian Xie1 and  Xinbing Sui1, 3*
  • 1Hangzhou Normal University, China
  • 2Department of Hepatobiliary Pancreatic Surgery, Sun Yat-sen University, China
  • 3Affiliated Hospital of Hangzhou Normal University, China

Ferroptosis is an iron-dependent, oxidative cell death, and is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. It has been implicated in various human diseases, including cancer. Recently, ferroptosis as a non-apoptotic form of cell death induced by small molecules is emerging in specific cancer types, however, its relevance in colorectal cancer (CRC) is unexplored and remains unclear. Here, we showed that ferroptosis inducer RSL3 initiated cell death and ROS accumulation in HCT116, LoVo and HT29 CRC cells over a 24 h time course. Furthermore, we determined that ROS levels and transferrin expression were elevated in CRC cells treated with RSL3 accompanied by a decrease in the expression of glutathione peroxidase 4 (GPX4), indicating an iron-dependent cell death, ferroptosis. Overexpression GPX4 resulted in decreased cell death after RSL3 treatment. Taken together, our results suggest that the induction of ferroptosis contributed to RSL3-induced cell death in CRC cells and ferroptosis may be a pervasive and dynamic form of cell death for cancer treatment.

Keywords: RSL3, ferroptosis, Glutathione peroxidase 4, GPx4, Reactive oxygen species (ROS, colorectal cancer

Received: 19 Sep 2018; Accepted: 08 Nov 2018.

Edited by:

Zhi Sheng, Virginia Tech, United States

Reviewed by:

Frank Arfuso, Curtin University, Australia
Vijay Pandey, Cancer Science Institute of Singapore, National University of Singapore, Singapore  

Copyright: © 2018 Zhang, Lin, Liu, Duan, Zhai, Zhang, Han, Xiang, Huang, Xie and Sui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Xinbing Sui, Hangzhou Normal University, Hangzhou, China, hzzju@zju.edu.cn