The interplay between apoptosis and ferroptosis mediated by ER stress
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LETTER TO THE EDITOR
The interplay between apoptosis and ferroptosis mediated by ER stress Go J. Yoshida1,2 Accepted: 25 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Keywords Apoptosis · Erastin · ER stress · Ferroptosis · Mitochondria I read with great interest the work by Lee et al., in which apoptotic agent TRAIL in combination with erastin significantly induces apoptosis with oligomerization of Bax and disruption of mitochondrial membrane potential [1]. Notably, Bax proteins are more effective than Bak in the combined treatment-enhanced apoptosis. Intriguingly, the combination treatment-promoted apoptosis is not effectively inhibited in BAK-deficient cancer cells, but in BAX-deficient cancer cells. Moreover, BID knockdown results in the suppression of apoptosis induced by the combined treatment. It is plausible that BH3-only proteins such as BID play an important role in the activation of Bax during the combined treatment. Simultaneous treatment with both erastin and TRAIL increases pro-apoptotic Bax oligomers, which are localized in mitochondrial outer membrane and cause cytochrome c release and caspase activation [1, 2]. Remarkably, the authors previously reported that erastin induces endoplasmic reticulum (ER) stress, and p53-independent C/ EBP-homologous protein (CHOP)/ p53 upregulated modulator of apoptosis (PUMA) pathway is responsible for the combination treatment-induced synergistic apoptosis. ER stress induces apoptosis by expressing pro-apoptotic proteins such as PUMA, NOXA, GADD34, ERO1α, and BIM. The combined treatment with ferroptosis inhibitor and TRAIL fails to inhibit ER stress-induced apoptosis [3]. Eratin has been identified as a novel compound to induce ferroptosis. Ferroptosis is a form of necrotic cell death characterized by the oxidative modification of phospholipid * Go J. Yoshida go‑[email protected] 1
Department of Immunological Diagnosis, Juntendo University School of Medicine, Tokyo, Japan
Department of Pathology and Oncology, Juntendo University School of Medicine, 2‑1‑1 Hongo, Bunkyo‑ku, 113‑8421 Tokyo, Japan
2
membranes mediated by an iron-dependent mechanism. During the process of ferroptosis, there are no nuclear morphological changes, DNA fragmentation, caspase activation, and importantly this process cannot be reversed by caspase inhibitors [4]. Erastin selectively kills mutated RAS-driven cancer cells such as pancreatic ductal adenocarcinoma and colorectal adenocarcinoma. Erastin is the prototype ferroptosis inducer which decreases reduced glutathione (GSH) levels by directly inhibiting system Xc(-), which is composed of xCT cystine antiporter and CD98 heavy chain. However, erastin also has another target, voltage-dependent anion channels (VDACs), which induces mitochondrial dysfunction. Increased activity of RAS-RAF-MEK pathway or p53 expression is likely to elevate the generation of reactive oxygen species (ROS) mediated by mitochondrial VDAC2/3 or inhibit cystine uptake, respectively, and sensitize cancer cells to ferr
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