Abstract
Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in MYCN-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of SLC3A2 (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that MYCN-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (R-S-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, MYCN-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of MTAP. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in MYCN-amplified neuroblastoma.
Highlights
Both the evasion of cell death and dysregulated metabolism are hallmarks of cancer [1]
While we did not detect cystathionine by mass spectrometry in these samples, we evaluated the DepMap portal metabolites dataset where cystathionine was quantified across hundreds of cancer cell lines
This was consistent with a substantial increase of cystathionine beta-synthase (CBS) in MYCN-amplified NB compared to wild-type tumors (Fig. 2A), was not the result of MYCN binding to the promoter of CBS (Fig. 2B)
Summary
Both the evasion of cell death and dysregulated metabolism are hallmarks of cancer [1]. Ferroptosis is characterized by the iron (Fe)-dependent accumulation of reactive oxygen species (ROS), leading to excessive lipid peroxidation and cell death [4, 5]. In addition to its contributions to biological pathways, iron increases cellular ROS through the Fenton reaction, leading to the generation of lipid peroxides. The accumulation of these lipid peroxides is counteracted by the glutathione (GSH)-dependent peroxidase, GPX4, which converts lipid peroxides into non-toxic lipid alcohols [9]. We recently reported that MYCN sensitizes NB to cystine withdrawal and MYCN binds to and upregulates SLC3A2 and increases GSH levels [7], presumably to increase cysteine to counteract increased ROS from Fenton reactions. We perform mass spectrometry metabolomics to better understand the regulation of cysteine by MYCN in NB, and to determine whether the transsulfuration pathway contributes cysteine
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