Chemistry

Integrated stress response

Cancer cell

Cancer research

Biochemistry

Cell

CHOP

Downregulation and upregulation

Puma

Biology

Gene

Endoplasmic reticulum

Apoptosis

Programmed cell death

Cell biology

Cancer

Signal transduction

Messenger RNA

Translation (biology)

ATF4

Unfolded protein response

Genetics

Molecular Cancer Research

Since its discovery in 2012, ferroptosis has been well characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses. It is known as an iron-dependent form of programmed cell death, which is distinct from other forms of cell death such as apoptosis and necrosis. Nonetheless, little is known about the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and its role in cell death. Recent studies reveal that the ferroptotic agent-induced ER stress response plays an important role in the cross-talk between ferroptosis and other types of cell death. Ferroptotic agents induce the unfolded protein response and subsequently ER stress–mediated activation of the PERK–eIF2α–ATF4–CHOP pathway. CHOP (C/EBP homologous protein) signaling pathway–mediated p53-independent PUMA (p53 upregulated modulator of apoptosis) expression is involved in the synergistic interaction between ferroptosis and apoptosis. This review highlights the recent literature on ferroptotic and apoptotic agent interactions through the ER stress–mediated PERK–eIF2α–ATF4–CHOP–PUMA pathway and implicates combined treatment to effectively enhance tumoricidal efficacy as a novel therapeutic strategy for cancer. Mol Cancer Res; 16(7); 1073–6. ©2018 AACR.

Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis