Ferroptosis: the vulnerability within a cancer monster
Wanqing Xie, … , Shivani Agarwal, Jindan Yu
Wanqing Xie, … , Shivani Agarwal, Jindan Yu
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e170027. https://doi.org/10.1172/JCI170027.
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Commentary

Ferroptosis: the vulnerability within a cancer monster

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.

Authors

Wanqing Xie, Shivani Agarwal, Jindan Yu

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Figure 1

RB1 loss sensitizes cancer cells to GPX4 inhibitors by tilting the balance between the pro- and antiferroptosis effects of ACSL4 and GPX4, respectively.

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RB1 loss sensitizes cancer cells to GPX4 inhibitors by tilting the bala...
Ferroptosis is an iron- and ROS-dependent cell death pathway that is tightly controlled by two opposing enzymes, ACSL4 and GPX4. Respectively, ACSL4 and GPX4 induce and deplete lipid peroxidation, a prerequisite for ferroptosis. (A) In RB1-intact cells, ACSL4 expression is nearly undetectable due to the lack of E2F1-mediated transcriptional activation, resulting in a low level of PUFA-PLs. Due to this weak ferroptotic potential, the cells do not undergo notable ferroptosis, even when GPX4 function is inhibited. (B) Upon RB loss, E2F transcription factors induce ACSL4 expression, resulting in PUFA-PL accumulation and a high ferroptotic potential, which is kept in check by GPX4 that is abundantly expressed in most cancer cells and protects the cells from autonomous ferroptosis. However, this strong ferroptotic potential is unblocked when RB1-deficient cells are treated with GPX4 inhibitors, resulting in massive ferroptosis and cell death.