A critical review of advances in tumor metabolism abnormalities induced by nitrosamine disinfection by-products in drinking water.

Intensified sanitation practices amid the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, whereas chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed.

Zinc deficiency drives ferroptosis resistance by lactate production in esophageal squamous cell carcinoma.

Trace metal zinc is involved in key processes of solid tumors by its antioxidant properties, while the role of zinc at the onset of esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to determine whether zinc is associated with the ESCC and underlying molecular events involving malignant progression. Based on a case-control study, we found serum and urine zinc were decreased and correlated with ESCC progression. Thus, an in vitro model for zinc deficiency (ZD) was established, and we found that ZD contributed to the proliferation, migration, and invasion of EC109 cells. Untargeted metabolomics identified 59 upregulated metabolites and 6 downregulated metabolites, among which glycolysis and ferroptosis-related oxidation of chain fatty acids might play crucial steps in ZD-treated molecular events. Interestingly, ZD disrupted redox homeostasis and enhanced cytosolic Fe2+ of EC109 cells, while lipid peroxidation, the key marker of ferroptosis occurrence, was decreased after ZD treatment. The mechanism underlying these changes may involve ZD-enhanced ESCC glycolysis and lactate production, which confer ferroptosis resistance by inhibiting of p-AMPK and leading to the upregulation of SREBP1 and SCD1 to enhance the production of anti-ferroptosis monounsaturated fatty acids.

Synergism of Fusobacterium periodonticum and N-nitrosamines promote the formation of EMT subtypes in ESCC by modulating Wnt3a palmitoylation.

N-Nitrosamine disinfection by-products (NAs-DBPs) have been well proven for its role in esophageal carcinogenesis. However, the role of intratumoral microorganisms in esophageal squamous cell carcinoma (ESCC) has not yet been well explored in the context of exposure to NAs-DBPs. Here, the multi-omics integration reveals F. periodonticum (Fp) as "facilitators" is highly enriched in cancer tissues and promotes the epithelial mesenchymal transition (EMT)-like subtype formation of ESCC. We demonstrate that Fp potently drives de novo synthesis of fatty acids, migration, invasion and EMT phenotype through its unique FadAL adhesin. However, N-nitrosomethylbenzylamine upregulates the transcription level of FadAL. Mechanistically, co-immunoprecipitation coupled to mass spectrometry shows that FadAL interacts with FLOT1. Furthermore, FLOT1 activates PI3K-AKT/FASN signaling pathway, leading to triglyceride and palmitic acid (PA) accumulation. Innovatively, the results from the acyl-biotin exchange demonstrate that FadAL-mediated PA accumulation enhances Wnt3A palmitoylation on a conserved cysteine residue, Cys-77, and promotes Wnt3A membrane localization and the translocation of ß-catenin into the nucleus, further activating Wnt3A/ß-catenin axis and inducing EMT phenotype. We therefore propose a "microbiota-cancer cell subpopulation" interaction model in the highly heterogeneous tumor microenvironment. This study unveils a mechanism by which Fp can drive ESCC and identifies FadAL as a potential diagnostic and therapeutic target for ESCC.