Biology subjects

Setayeshpour, Y.

Publications and source records attributed to Setayeshpour, Y..

3 recordsLinked to original sources

bioRxiv2024

Ascitic fluid protects against ferroptosis and enables the peritoneal spread of ovarian cancer

One of the most common sites of metastasis in ovarian cancer (OVCA) is the peritoneum. Often, this spread is accompanied by the accumulation of a fluid called ascites in the peritoneal cavity. Despite its common occurrence in metastatic OVCA patients, ascites and its influence on the peritoneal spread of OVCA are poorly understood. Interestingly, OVCA cells are vulnerable to ferroptosis, a type of cell death caused by lipid peroxidation. Hence, how these ferroptosis-sensitive OVCA cells persist in their spread to the peritoneum remains unknown. Here, we show that ascites robustly protects OVCA cells and patient-derived organoids against ferroptosis and enhances the peritoneal spread of OVCA cells in mice. Mechanistically, ascites downregulates the mitochondrial enzyme, 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which contributes to an increase in lipid droplets. Additionally, upon ferroptosis induction, ascites represses the upregulation of the transferrin receptor, TFRC, thereby decreasing cellular labile iron levels. Furthermore, we show that lipid-lowering fibrates reverse cellular changes induced by ascites, and they attenuate the peritoneal spread of OVCA cells in mice. Our findings implicate the importance of ascites in ferroptosis protection and the peritoneal spread of OVCA, and they suggest that targeting the ferroptosis protection by ascites may present a novel therapeutic approach to limit OVCA metastasis.

cancer biology↗

bioRxiv2024

Protein CoAlation on TXNRD2 regulates mitochondrial thioredoxin system to protect against ferroptosis

The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its in vitro enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

cell biology↗

bioRxiv2024

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhanced cystine uptake, and contributed to elevated CoA and GSH levels, collectively contributing to ferroptosis protection. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/581432v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@9fa073org.highwire.dtl.DTLVardef@1df0137org.highwire.dtl.DTLVardef@1c8e8cborg.highwire.dtl.DTLVardef@12b76b3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗