SLC43A2 and NFκB signaling pathway regulate methionine/cystine restriction-induced ferroptosis in esophageal squamous cell carcinoma via a feedback loop

Abstract

Studies have indicated dietary restriction of methionine/cystine provided a therapeutic benefit in diseases such as cancer. However, the molecular and cellular mechanisms that underlie the interaction between methionine/cystine restriction (MCR) and effects on esophageal squamous cell carcinoma (ESCC) have remained elusive. Here, we discovered the dietary restriction of methionine/cystine has a large effect on cellular methionine metabolism as assayed in a ECA109 derived xenograft model. RNA-seq and enrichment analysis suggested the blocked tumor progression was affected by ferroptosis, together with the NFκB signaling pathway activation in ESCC. Consistently, GSH content and GPX4 expression were downregulated by MCR both in vivo and in vitro. The contents of Fe2+ and MDA were negatively correlated with supplementary methionine in a dose-dependent way. Mechanistically, MCR and silent of SLC43A2, a methionine transporter, diminished phosphorylation of IKKα/β and p65. Blocked NFκB signaling pathway further decreased the expression of SLC43A2 and GPX4 in both mRNA and protein level, which in turn downregulated the methionine intake and stimulated ferroptosis, respectively. ESCC progression was inhibited by enhanced ferroptosis and apoptosis and impaired cell proliferation. In this study, we proposed a novel feedback regulation mechanism underlie the correlation between dietary restriction of methionine/cystine and ESCC progression. MCR blocked cancer progression via stimulating ferroptosis through the positive feedback loop between SLC43A2 and NFκB signaling pathways. Our results provided the theoretical basis and new targets for ferroptosis-based clinical antitumor treatments for ESCC patients.

Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy

“…Importantly, SLC43A2 increases the phosphorylation of IKKα/β and p65, and NF-κB silencing leads to inhibition of SLC43A2 and GPX4 in both mRNA and protein levels, thereby downregulation of methionine uptake. Following these changes, ferroptosis and apoptosis are induced and esophageal squamous cell carcinoma progression is impaired [ 215 ]. In a novel study, CRISPR/Cas9 system carrying in nanoplatforms was used to decrease methionine intake by cancer cells via inhibiting SLC43A2.…”

Identification and Validation of Immune Implication of R-Spondin 1 and an R-Spondin 1-Related Prognostic Signature in Esophagus Cancer

“…Chemotherapy is the main treatment method for ESCA, and resistance to chemotherapeutic drugs is an important obstacle to effective treatment. However, HMGA1 can drive chemotherapy resistance in ESCA by inhibiting ferroptosis [3]. Extracellular vesicles (EVs) are small extracellular vesicles.…”

Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

“…Due to the high proliferative rate, cancer cells mainly depend on the methionine cycle for methylation reaction as well as the production of H 2 S and GSH [ 10 ]. A study found that cancer cells express high levels of methionine transporter SLC43A2 for the consumption of more methionine, which causes cancer progression [ 11 ]. Many studies found that a methionine restriction diet can reduce cancer risk and progression through various molecular processes [ 10 , 12 , 13 ].…”