Ferroptosis: the vulnerability within a cancer monster

• Type of Material: Article
• Authors: Wanqing Xie, Emory University; Shivani Agarwal, Northwestern University; Jindan Yu, Emory University
• Language: English
• Date: 2023-05-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Xie et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI170027
• Title of Journal or Parent Work: Journal of Clinical Investigation
• Volume: 133
• Issue: 10
• Keywords: Cell Line, Tumor; Lipid Peroxidation; Ferroptosis; Humans; Male; Neuroendocrine Tumors
• Research Categories: Health Sciences, Oncology

Abstract

Treatment-resistant cancer, such as neuroendocrine prostate cancer (NEPC), is a lethal disease with limited therapeutic options. RB1 is a tumor suppressor gene that is lost in a majority of NEPC tumors. In this issue of the JCI, Wang and colleagues examined how RB1 loss may sensitize cancer cells to ferroptosis inducers through elevation of ACSL4, a key enzyme that promotes lipid peroxidation and triggers ferroptosis. We discuss a high potential of RB1-deficient cells to undergo ferroptosis due to the elevation of ACSL4. This is normally kept in check by abundant expression of GPX4, an antioxidant enzyme, in cancer cells. This balance, however, is tilted by GPX4 inhibitors, leading to massive ferroptosis. We highlight possible therapeutic strategies that exploit this inherent vulnerability for targeting RB1-deficient, treatment-resistant cancer.