Proteomic Analysis Identifies Multiple Mechanisms of 5-Fluorouracil-Induced Gut Mucositis in Mice.

Ivanov, Sergey M.; Zgoda, Victor G.; Isakova, Valeria A.; Trukhanova, Lyubov S.; Poroikov, Vladimir V.; Shtil, Alexander A.

Simple Summary: One serious limitation of the efficacy of anticancer chemotherapy is the inevitable injury of non-malignant tissues. Side effects of 5-fluorouracil (5-FU), a drug widely used in treatment regimens for decades, are not an exception. Severe damage of the internal gut milieu, a state generally described by the term 'mucositis', is most unfavorable for the patient. This study presents an animal model for the analysis of molecular events attributable to the pathogenesis of 5-FU-induced gut mucositis. Our experiments and bioinformatics calculations indicated that this state is associated with a plethora of time-dependent changes in the intestine and the colon. These changes are directed at the coordination of the damage-related massive proteolysis combined with compensatory catabolic processes. Our findings uncovered new and counterintuitive mechanisms relevant to the rational design of pharmacological gut protectors during antitumor chemotherapy. Background/Objectives. Damage of the gastrointestinal mucosa is a major side effect of the anticancer drug 5-fluorouracil (5-FU). Insight into the molecular pathogenesis of 5-FU-induced gut mucositis is expected to justify the strategies of prophylaxis. Methods. We analyzed intestinal specimens obtained from Balb/c mice treated with 70 mg/kg 5-FU daily for up to 6 days. Results. Manifestations of mucositis in the ileum and the colon included diarrhea, weight loss, and morphological lesions. The proteomic analysis revealed dozens of differentially expressed proteins governed by a set of master regulator proteins that regulated downstream pathways culminating in the complexes of specific transcription factors. Among the most important mechanisms of 5-FU-induced gut damage predicted by bioinformatics tools was stimulation of insulin-like growth factor 1 concomitant with inhibition of insulin receptor substrate 1, suggesting an involvement of the insulin pathway. Furthermore, the levels of 14-3-3γ protein and epinephrin B2 tyrosine kinase were interpreted as key inhibitory effects of 5-FU. These changes were detectable in the ileum as well as in the colon, pointing to the commonality of 5-FU responses across the gut. Conclusion. These results demonstrated a hierarchical network of gut injury mechanisms differentially regulated in the course of the emergence of 5-FU-induced mucositis.

PROTEIN metabolism; INTESTINAL injuries; MUCOSITIS; INTESTINES; CARRIER proteins; RESEARCH funding; TRANSCRIPTION factors; ILEUM; MICE; BIOINFORMATICS; COLON (Anatomy); PROTEOMICS; ANIMAL experimentation; METABOLISM; PROTEIN-tyrosine kinases; FLUOROURACIL; SOMATOMEDIN; SYMPTOMS

Cancers, 2024, Vol 16, Issue 23, p4025

2072-6694

Academic Journal

10.3390/cancers16234025